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Böbrek Hücreli Karsinomlu Hastaların Demografik Özellikleri ve Tedavi Sonuçları: Tek Merkez Deneyimi

Year 2016, Volume: 16 Issue: 2, 0 - 0, 20.05.2016

Arife Ulaş Burak Bilgin Didem Şener Dede F. Tuğba Köş Muhammed Bülent Akıncı Mehmet Ali Nahit Şendur Bülent Yalçın

https://doi.org/10.17098/amj.61112
Cited By: 1

Abstract

Amaç: Çalışmanın amacı, böbrek hücreli karsinomlu (BHK) hastaların demografik özellikleri ve tedavi sonuçlarını değerlendirmektir.

Materyal-Metot:  2005- 2014 yılları arasında Ankara Atatürk Eğitim ve Araştırma Hastanesi’nde BHK tanısı ile takip edilen 100 hastaya ait veriler geriye dönük olarak incelendi. Sağkalım analizi için Kaplan–Meier yöntemi kullanıldı.

Bulgular: Hastaların ortanca yaşı 62 (25.0 -89.0) olup, %40’ı 65 yaş üstündeydi.  Erkek / kadın  hasta  oranı  2.1 olarak saptandı. Hastaların %64’üne radikal nefrektomi, %7’sine parsiyel nefrektomi uygulanmıştı. Histopatolojik olarak berrak hücreli tip  %84 oranındaydı. Çoğunluğunu evre IV hastalar oluşturmaktaydı (%55.0) ve en sık metastaz bölgesi akciğerdi (%34).  Hastaların 62’si metastaz sonrası ilk basamakta interferon (IFN) tedavisi, IFN sonrası tirozin kinaz inhibitörünü (TKI) ise 49 hasta almıştı. Tüm hastaların ortanca takip süresi 24 ay ve ortanca genel sağkalım (GS) 36 ay idi. Sunitinib kullanan hastalarda ise ortanca GS 30.0 ay ve ortanca progresyonsuz sağkalım (PS) 15 ay bulundu. Sunitinib tedavisi sırasında hastaların %53.8’inda doz azaltımı yapıldı ve %36.6’sında tedaviye ara verildi. Grade 3-4 toksisiteler içinde en sık halsizlik (%34.9) ve anemi (%27.9) saptandı. Sunitinib kullanan hastalarda Memorial Sloan Kettering Cancer Center (MSKCC) kriterlerine göre iyi, orta, kötü riskli hastalarda ortanca PS’ler ise sırasıyla 45, 15 ve 6 ay idi (p=0.05). Çok değişkenli analizde  yaşın 65’in üstünde olması (p=0.04), gradın 3-4 olması (p=0.05) ve  MSKCC kriterlerine (sunitinib için) göre kötü riskli olmanın (p=0.04) GS’ı kısalttığı saptandı.   

Sonuç: Çalışmamızda hastalarımızın çoğu erkek, 65 yaşından genç ve tanıda ileri evredeydi. Kliniğimizde takip ettiğimiz BHK’li nefrektomi geçiren hastalarda ve metastatik aşamada bir TKI olan sunitinib kullanan hastalarda sağkalım sürelerinde belirgin iyileşme olduğu gözlendi. 

Keywords

böbrek hücreli kanser tirozin kinaz inhibitör sunitinib

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1):5-29.
  • Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009;28;373(9669):1119-32.
  • Escudier B, EisenT, Porta C, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii49-56.
  • Ebele JN, Sauter G, Epstein JI. Pathology and genetics of tumours of the urinary system and male genital organs. World Health Organisation classification of tumours International Agency for Research on Cancer. France: Lyon; 2004.
  • Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcino-ma and management of recurrent disease. Urol Clin North Am 2003;30:843-52.
  • Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704.
  • Law TM, Motzer RJ, Mazumdar M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995;76(5):824-32.
  • Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
  • Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34.
  • Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28(13):2144–50.
  • Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271–81.
  • Motzer RJ, Escudier B, Oudard S, et al. RECORD‐1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116(18):4256-65.
  • Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, inpatients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16–24.
  • Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584–90.
  • Sobin LH, Gospodarowicz, Wittekind CH, eds. TNM classification of malignant tumors. 7th ed. New York: Wiley-Liss; 2009:193-5.
  • Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205-16.
  • Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. May 28, 2009, U.S Department of Health and Human Services; National Institutes of Health; National Cancer Institute. Available from URL: http://evs.nci.nih.gov/ftp1/.CTCAE/CTCAE_4.03_2010-06-14. (Date of Access:25 Dec, 2015).
  • Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454-63.
  • Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal carcinoma in the United States: trends from the Surveillance, Epidemiology, and End Results program. The Journal of Urology 2006; 176(6 Pt 1):2397–400.
  • Aron M, Nguyen MM, Stein RJ, Gill IS. Impact of gender in renal cell carcinoma: an analysis of the SEER database. European Urology 2008;54(1):133–40.
  • Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): a systematic review of the literature. Crit Rev Oncol Hematol 2015;94(2):238-50.
  • Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163(4):1090-5.
  • Garnick MB. Primary neoplasms of the kidney. In: Brady HR, Wilcox CS, editors. Therapy in nephrology and hypertension: a companion to Brenner and Rector's the kidney. Philadelphia, Pa: WB Saunders; 1998: pp. 337-41.
  • Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer 1971;28:1165-77.
  • Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. Cancer J Clin 2005;55:10.
  • Heng DY, Choueiri TK, Rini BI, Lee J, Yuasa T, Pal SK, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol 2014;25(1): 149-54.
  • Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17(8):2530.
  • Van der Veldt AAM, Meijerink MR, van den Eertwegh AJM, Boven E. Targeted therapies in renal cell cancer: recent developments in imaging. Target Oncol 2010; 5: 95–112.
  • Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as fi rst-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30(12):1371-7.
  • Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009;10(8):757-63.
  • Schnadig ID, Hutson TE, Chung H, Dhanda R, Halm M, Forsyth M, et al. Dosing patterns, toxicity, and outcomes in patients treated with first line sunitinib for advanced renal cell carcinoma in community-based practices. Clin Genitourin Cancer 2014;12(6):413-21.
  • Ravaud A, Bello CL. Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice. Anticancer Drugs 2011;22:377-83.
  • Rini BI, Escudier BJ, Michaelson MD, et al. Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy. ASCO Meeting Abstracts 2012; 30(5 Suppl):354.
  • Najjar YG, Mittal K, Elson P, Wood L, Garcia JA, Dreicer R, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084-89.
  • Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol 2014;32:480-7.

Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience

Year 2016, Volume: 16 Issue: 2, 0 - 0, 20.05.2016

Arife Ulaş Burak Bilgin Didem Şener Dede F. Tuğba Köş Muhammed Bülent Akıncı Mehmet Ali Nahit Şendur Bülent Yalçın

https://doi.org/10.17098/amj.61112
Cited By: 1

Abstract

Objectives: The aim of the study was to evaluate demographic characteristics and treatment outcomes of patients with renal cell cancer. 

Materials and Methods: Data of 100 patients diagnosed with RCC at Atatürk Research and Education Hospital between the years 2005-2014 are analyzed retrospectively. Kaplan-Meier test were performed for survival analysis. 

Results: Median age of patients was 62 (25-89) and 40% of the population was over 65 years old. Sex ration (male/female)  was 2/1. Radical nephrectomy was perfomed 64 % of patients also partial nephrectomy rate was 7%.  Histopathologically, clear cell varient’s rate was 84 %. Most of the patients were stage 4 (55%)  and the most common metastatic site was lung (34%). After the development of metastases, first line interferone (IFN) treatment was administered to 62 of patients and 49 of these took tirosine kinase inhibitor after IFN treatment. For all patients, median follow-up time was 24 months and median overall survival (OS) was 36 months. We determined that OS was 30 months and progression free survival (PFS) was 15 months among patients had recieved sunitinib. During sunitinib treatment, dose reduction was performed in 53.8% of the patients and treatment was interrupted in 36.6% of the patients. Fatigue (34.9%) and anemia (27.9%) were the most common grade 3-4 toxicities. In patients who used sunitinib, median PFS in the good, intermediate and poor risk patients according to Memorial Sloan Kettering Cancer Center (MSKCC) criteria respectively were 45, 15 and 6 months (p=0.05). In multivariate analysis, we found that age over 65 years  (p=0.04),  grade 3-4 tumors (p=0.05) and the poor risk according to MSKCC criteria (p=0,04) are associated with decreased overall survival.

Conclusion: The majority of our patients were male, younger than 65 years and had advanced disease at diagnosis. The significantly improvement in survival has been observed between the nephrectomized and metastatic RCC patients who used sunitinib at our clinic.

Keywords

Renal cell cancer tyrosine kinase inhibitor sunitinib

References

  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1):5-29.
  • Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009;28;373(9669):1119-32.
  • Escudier B, EisenT, Porta C, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii49-56.
  • Ebele JN, Sauter G, Epstein JI. Pathology and genetics of tumours of the urinary system and male genital organs. World Health Organisation classification of tumours International Agency for Research on Cancer. France: Lyon; 2004.
  • Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcino-ma and management of recurrent disease. Urol Clin North Am 2003;30:843-52.
  • Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2014;66:704.
  • Law TM, Motzer RJ, Mazumdar M, et al. Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995;76(5):824-32.
  • Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
  • Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356(2):125–34.
  • Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28(13):2144–50.
  • Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271–81.
  • Motzer RJ, Escudier B, Oudard S, et al. RECORD‐1 Study Group. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116(18):4256-65.
  • Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, inpatients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:16–24.
  • Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584–90.
  • Sobin LH, Gospodarowicz, Wittekind CH, eds. TNM classification of malignant tumors. 7th ed. New York: Wiley-Liss; 2009:193-5.
  • Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92(3):205-16.
  • Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. May 28, 2009, U.S Department of Health and Human Services; National Institutes of Health; National Cancer Institute. Available from URL: http://evs.nci.nih.gov/ftp1/.CTCAE/CTCAE_4.03_2010-06-14. (Date of Access:25 Dec, 2015).
  • Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454-63.
  • Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal carcinoma in the United States: trends from the Surveillance, Epidemiology, and End Results program. The Journal of Urology 2006; 176(6 Pt 1):2397–400.
  • Aron M, Nguyen MM, Stein RJ, Gill IS. Impact of gender in renal cell carcinoma: an analysis of the SEER database. European Urology 2008;54(1):133–40.
  • Abdel-Rahman O, Fouad M. Efficacy and toxicity of sunitinib for non clear cell renal cell carcinoma (RCC): a systematic review of the literature. Crit Rev Oncol Hematol 2015;94(2):238-50.
  • Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163(4):1090-5.
  • Garnick MB. Primary neoplasms of the kidney. In: Brady HR, Wilcox CS, editors. Therapy in nephrology and hypertension: a companion to Brenner and Rector's the kidney. Philadelphia, Pa: WB Saunders; 1998: pp. 337-41.
  • Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF. Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer 1971;28:1165-77.
  • Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. Cancer J Clin 2005;55:10.
  • Heng DY, Choueiri TK, Rini BI, Lee J, Yuasa T, Pal SK, et al. Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials. Ann Oncol 2014;25(1): 149-54.
  • Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17(8):2530.
  • Van der Veldt AAM, Meijerink MR, van den Eertwegh AJM, Boven E. Targeted therapies in renal cell cancer: recent developments in imaging. Target Oncol 2010; 5: 95–112.
  • Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as fi rst-line therapy for advanced renal cell carcinoma. J Clin Oncol 2012;30(12):1371-7.
  • Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009;10(8):757-63.
  • Schnadig ID, Hutson TE, Chung H, Dhanda R, Halm M, Forsyth M, et al. Dosing patterns, toxicity, and outcomes in patients treated with first line sunitinib for advanced renal cell carcinoma in community-based practices. Clin Genitourin Cancer 2014;12(6):413-21.
  • Ravaud A, Bello CL. Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice. Anticancer Drugs 2011;22:377-83.
  • Rini BI, Escudier BJ, Michaelson MD, et al. Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy. ASCO Meeting Abstracts 2012; 30(5 Suppl):354.
  • Najjar YG, Mittal K, Elson P, Wood L, Garcia JA, Dreicer R, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014;50:1084-89.
  • Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol 2014;32:480-7.
There are 35 citations in total.

Details

Journal Section Research Articles
Authors

Arife Ulaş

Burak Bilgin This is me

Didem Şener Dede This is me

F. Tuğba Köş This is me

Muhammed Bülent Akıncı This is me

Mehmet Ali Nahit Şendur This is me

Bülent Yalçın This is me

Publication Date May 20, 2016
Published in Issue Year 2016 Volume: 16 Issue: 2

Cite

APA Ulaş, A., Bilgin, B., Dede, D. Ş., Köş, F. T., et al. (2016). Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience. Ankara Medical Journal, 16(2). https://doi.org/10.17098/amj.61112
AMA Ulaş A, Bilgin B, Dede DŞ, Köş FT, Akıncı MB, Şendur MAN, Yalçın B. Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience. Ankara Med J. May 2016;16(2). doi:10.17098/amj.61112
Chicago Ulaş, Arife, Burak Bilgin, Didem Şener Dede, F. Tuğba Köş, Muhammed Bülent Akıncı, Mehmet Ali Nahit Şendur, and Bülent Yalçın. “Demographic Characteristics and Treatment Outcomes of Patients With Renal Cell Cancer: Single Center Experience”. Ankara Medical Journal 16, no. 2 (May 2016). https://doi.org/10.17098/amj.61112.
EndNote Ulaş A, Bilgin B, Dede DŞ, Köş FT, Akıncı MB, Şendur MAN, Yalçın B (May 1, 2016) Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience. Ankara Medical Journal 16 2
IEEE A. Ulaş, “Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience”, Ankara Med J, vol. 16, no. 2, 2016, doi: 10.17098/amj.61112.
ISNAD Ulaş, Arife et al. “Demographic Characteristics and Treatment Outcomes of Patients With Renal Cell Cancer: Single Center Experience”. Ankara Medical Journal 16/2 (May 2016). https://doi.org/10.17098/amj.61112.
JAMA Ulaş A, Bilgin B, Dede DŞ, Köş FT, Akıncı MB, Şendur MAN, Yalçın B. Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience. Ankara Med J. 2016;16. doi:10.17098/amj.61112.
MLA Ulaş, Arife et al. “Demographic Characteristics and Treatment Outcomes of Patients With Renal Cell Cancer: Single Center Experience”. Ankara Medical Journal, vol. 16, no. 2, 2016, doi:10.17098/amj.61112.
Vancouver Ulaş A, Bilgin B, Dede DŞ, Köş FT, Akıncı MB, Şendur MAN, Yalçın B. Demographic Characteristics and Treatment Outcomes of Patients with Renal Cell Cancer: Single Center Experience. Ankara Med J. 2016;16(2).

Cited By

BÖBREK TÜMÖRÜ VAKALARININ RETROSPEKTİF OLARAK DEĞERLENDİRİLMESİ
Kırıkkale Üniversitesi Tıp Fakültesi Dergisi
Tuba DEVRİM
https://doi.org/10.24938/kutfd.552211