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Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?

Yıl 2021, Cilt: 14 Sayı: 2, 416 - 427, 01.04.2021
https://doi.org/10.31362/patd.846610

Öz

Amaç: Meme kanserinde, trucut iğne biyopsi (TİB) ve rezeksiyon materyalleri arasında, tanısal uyum, histolojik derece, moleküler alt tipleri, östrojen reseptörü (ER), progesteron reseptörü (PgR) ve insan epidermal büyüme faktörü reseptörü 2 (HER2) düzeylerinin karşılaştırılarak sonuçların literatür eşliğinde değerlendirilmesi amaçlanmıştır.
Gereç ve yöntem: 2018 Mayıs-2020 Kasım tarihleri arasında, Pamukkale Üniversitesi Tıp Fakültesi Patoloji Anabilim Dalı’nda tanı almış 64 olguya ait TİB ve aynı hastaların rezeksiyon materyalleri çalışmaya alınmıştır. Tümör tipi, derecesi, moleküler alt tipleri ve immunohistokimyasal olarak ER, PgR, HER2, Ki-67 ve moleküler FISH yöntemi ile HER2 durumuna ait patolojik bilgiler retrospektif olarak incelenmiştir.
Bulgular: TİB ile rezeksiyon materyallerinin histolojik tipi arasındaki uyum oranı %93,75’tir. ER, PgR, HER2 uyum oranları sırasıyla, %89 (kappa, 0,685, p<0,001), %81,8 (kappa, 0,645, p<0,001), %95 (kappa=8,68, p<0,001)’tir. HER2 uyum oranı, ER ve PgR reseptör uyum oranına göre daha iyidir. Ki-67’ye baktığımızda %79 oranında, orta düzeyde uyum (kappa, 0,447, p<0,001) görülmüştür. Derece karşılaştırmasında %79 uyum oranı ile iyi uyum (kappa, 0,637, p<0,001) bulunmuştur. Moleküler sınıflama arasında uyum oranı %93 olup, çok iyi uyum (kappa, 0,882, p<0,001) bulunmuştur. Lüminal A en fazla görülen tip olup, uyum oranı %97’tür.
Sonuç: Tanısal biyopsi ve rezeksiyon materyalleri arasında yüksek oranda uyum görülmüştür. TİB’lerin tümörün histopatolojik özelliklerinin belirlenmesi, tanı, tedavi ve prognozda önemi olan ER, PgR, HER2, Ki-67 immünhistokimyasal boyamalarının çalışılması için güvenilir materyaller olduğu sonucuna varılmıştır. Ayrıca Ki-67, HER2 negatif tümörlerin moleküler subtiplemesinde önemli olduğu görülmüştür.

Kaynakça

  • 1. Al-Thoubaity FK. Molecular classification of breast cancer: A retrospective cohort study. Ann Med Surg (Lond). 2019 Dec 6;49:44-48. doi: 10.1016/j.amsu.2019.11.021.
  • 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum in: CA Cancer J Clin. 2020 Jul;70(4):313.
  • 3. Devrim T, Aydemir M. Comparison Of Hormone Receptors (Er/Pgr) And Her2 Values In Breast Cancer Biopsy And Resection Materials. Med J SDU 2020; 27(2): 154-159.
  • 4. Arnedos M, Nerurkar A, Osin P, A'Hern R, Smith IE, Dowsett M. Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC). Ann Oncol. 2009 Dec;20(12):1948-52. doi: 10.1093/annonc/mdp234. Epub 2009 Jul 1
  • 5. Senkus E, Kyriakides S, Ohno S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26(Suppl 5):v8–30.
  • 6. Pettine S, Place R, Babu S et al. Stereotactic breast biopsy is accurate, minimally invasive, and cost effective. Am J Surg 1996; 171: 474–476.
  • 7. Pijnappel RM, van Dalen A, Borel Rinkes IH et al. The diagnostic accuracy of core biopsy in palpable and non-palpable breast lesions. Eur J Radiol 1997; 24: 120–123.
  • 8. Tamaki K, Sasano H, Ishida T, Miyashita M, Takeda M, Amari M, et al. Comparison of core needle biopsy (CNB) and surgical specimens for accurate preoperative evaluation of ER, PgR and HER2 status of breast cancer patients. Cancer Sci. 2010 Sep;101(9):2074-9. doi: 10.1111/j.1349-7006.2010.01630.x.
  • 9. Jeong YS, Kang J, Lee J, Yoo TK, Kim SH, Lee A. Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer. J Pathol Transl Med. 2020 Jan;54(1):87-94. doi: 10.4132/jptm.2019.10.14. Epub 2019 Nov 13.
  • 10. Buck A, Schirrmeister H, Kühn T, Shen C, Kalker T, Kotzerke J, et al. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med 2002; 29:1317–23.
  • 11. Zhang J, Jia Z, Zhou M, Ragaz J, Zhang YP, Wang BY, et al. The SUVmax for 18F-FDG correlates with molecular subtype and survival of previously untreated metastatic breast cancer. Clin Nucl Med 2013;38:256-62.
  • 12. Lakhani SR, Ellis IO, Schnitt SJ et al. eds. World Health Organization classification of tumours of the breast. 5th ed. Lyon: IARC Press, 2019.
  • 13. Rosen PP. Rosen’s Breast Pathology, 3rd edn. Philadelphia, PA, USA: Lippincott Williams & Wilkins, 2009.
  • 14. Wolff AC, Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018; 36: 2105-22.
  • 15. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al.; Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013
  • 16. Shannon J, Douglas-Jones AG, Dallimore NS. Conversion to core biopsy in preoperative diagnosis of breast lesions. Is it justified by the results? J Clin Pathol 2001;54:762–5.
  • 17. Pettine S, Place R, Babu S et al. Stereotactic breast biopsy is accurate, minimally invasive, and cost effective. Am J Surg 1996; 171: 474–476.
  • 18. Pijnappel RM, van Dalen A, Borel Rinkes IH et al. The diagnostic accuracy of core biopsy in palpable and non-palpable breast lesions. Eur J Radiol 1997; 24: 120–123.
  • 19. Verkooijen HM, Peeters PH, Buskens E et al. Diagnostic accuracy of large-core needle biopsy for nonpalpable breast disease: a meta-analysis. Br J Cancer 2000; 82: 1017–1021.
  • 20. Dillon MF, Hill AD, Quinn CM et al. The accuracy of ultrasound, stereotactic, and clinical core biopsies in the diagnosis of breast cancer, with an analysis of false negative cases. Ann Surg 2005; 242: 701–707.
  • 21. Usami S, Moriya T, Amari M et al. Reliability of prognostic factors in breast carcinoma determined by core needle biopsy. Jpn J Clin Oncol 2007; 37: 250–5.
  • 22. Alkabban FM, Ferguson T. Cancer, Breast. StatPearls Publishing Treasure Island (FL). 2019.
  • 23. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014; 5: 412-424.
  • 24. Kunc M, Biernat W, Senkus-Konefka E. Estrogen receptor-negative progesterone receptor-positive breast cancer-"Nobody's land" or just an artifact? Cancer Treat Rev 2018;67:78-87.
  • 25. Damodaran D, Naidu BK, Varghese JC, Rajan P, Kuruvilla R, Kuruvilla S, et al.. A Prospective Study on Level of Concordance Between Core Needle Biopsy and Surgical Specimen for Assessing Oestrogen Receptor, Progesterone Receptor, and Her2/Neu Receptor Status in Carcinoma Breast and Its Implications on Treatment Decisions. Indian J Surg Oncol. 2020 Sep;11(3):446-450. doi: 10.1007/s13193-020-01146-y. Epub 2020 Jun 25.
  • 26. Asogan AB, Hong GS, Arni Prabhakaran SK. Concordance between core needle biopsy and surgical specimen for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status in breast cancer. Singapore Med J. 2017 Mar;58(3):145-149. doi: 10.11622/smedj.2016062. Epub 2016 Mar 31.
  • 27. Walter V, Fischer C, Deutsch TM, Ersing C, Nees J, Schütz F, et al. Estrogen, progesterone, and human epidermal growth factor receptor 2 discordance between primary and metastatic breast cancer. Breast Cancer Res Treat. 2020 Aug;183(1):137-144. doi: 10.1007/s10549-020-05746-8.
  • 28. Greer LT, Rosman M, Mylander WC, Hooke J, Kovatich A, Sawyer K, et al. Does breast tumor heterogeneity necessitate further immunohistochemical staining on surgical specimens? J Am Coll Surg. 2013 Feb;216(2):239-51.
  • 29. Meattini I, Bicchierai G, Saieva C, De Benedetto D, Desideri I, Becherini C, et al. Impact of molecular subtypes classification concordance between preoperative core needle biopsy and surgical specimen on early breast cancer management: Single-institution experience and review of published literature. Eur J Surg Oncol. 2017 Apr;43(4):642-648. doi: 10.1016/j.ejso.2016.10.025.
  • 30. Kondov B, Milenkovikj Z, Kondov G, et al. Presentation of the molecular subtypes of breast cancer detected by ımmunohistochemistry in surgically treated patients. Open Access Maced J Med Sci. 2018;6(6):961-967.
  • 31. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 2009;7(1- 2):4-13.
Yıl 2021, Cilt: 14 Sayı: 2, 416 - 427, 01.04.2021
https://doi.org/10.31362/patd.846610

Öz

Purpose: The aim of this study was to evaluate the the concordance rate of molecular subtypes histological grade, estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) levels between the diagnostic biopsy and resection materials in breast cancer, in the light of the literature.
Materials and methods: Trucut needle biopsy (TNB) and resection materials of 64 cases, diagnosed at Department of Pamukkale University Medical Faculty Pathology, between 2018 May and 2020 November were included in this study. Tumor type, degree and pathological information on ER, PgR, HER2, Ki-67, immunohistochemically and HER2 status by molecular FISH method were analyzed retrospectively.
Results: Concordance rate between resection specimens and trucut needle biopsy is 93.75%. The concordance rates for ER, PgR, HER are 89% (kappa, 0.685, p<0.001), 81.8% (kappa, 0.645, p<0.001), 95% (kappa=8.68, p<0.001), respectively. HER2 concordance rates is better than ER and PgR receptor concordance rates. In Ki-67, a moderate agreement (kappa, 0.447, p<0.001) was observed at a rate of 79%. A good agreement 79% (kappa, 0.637, p<0.001) was found in the grade comparison. Concordance rate between molecular classification was 93% and very good agreement (kappa, 0.882, p<0.001) was found. Luminal A is the most common type and the concordance rate is 97%.
Conclusion: A high agreement was observed between diagnostic biopsy and resection materials. It was concluded that TIBs are reliable materials for determining the histopathological characteristics of the tumor, and studying the immunohistochemical staining of ER, PgR, HER2, Ki-67, which are important in diagnosis, treatment and prognosis. In addition, Ki-67 has been found to be important in molecular subtyping of HER2 negative tumors.


Kaynakça

  • 1. Al-Thoubaity FK. Molecular classification of breast cancer: A retrospective cohort study. Ann Med Surg (Lond). 2019 Dec 6;49:44-48. doi: 10.1016/j.amsu.2019.11.021.
  • 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum in: CA Cancer J Clin. 2020 Jul;70(4):313.
  • 3. Devrim T, Aydemir M. Comparison Of Hormone Receptors (Er/Pgr) And Her2 Values In Breast Cancer Biopsy And Resection Materials. Med J SDU 2020; 27(2): 154-159.
  • 4. Arnedos M, Nerurkar A, Osin P, A'Hern R, Smith IE, Dowsett M. Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC). Ann Oncol. 2009 Dec;20(12):1948-52. doi: 10.1093/annonc/mdp234. Epub 2009 Jul 1
  • 5. Senkus E, Kyriakides S, Ohno S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26(Suppl 5):v8–30.
  • 6. Pettine S, Place R, Babu S et al. Stereotactic breast biopsy is accurate, minimally invasive, and cost effective. Am J Surg 1996; 171: 474–476.
  • 7. Pijnappel RM, van Dalen A, Borel Rinkes IH et al. The diagnostic accuracy of core biopsy in palpable and non-palpable breast lesions. Eur J Radiol 1997; 24: 120–123.
  • 8. Tamaki K, Sasano H, Ishida T, Miyashita M, Takeda M, Amari M, et al. Comparison of core needle biopsy (CNB) and surgical specimens for accurate preoperative evaluation of ER, PgR and HER2 status of breast cancer patients. Cancer Sci. 2010 Sep;101(9):2074-9. doi: 10.1111/j.1349-7006.2010.01630.x.
  • 9. Jeong YS, Kang J, Lee J, Yoo TK, Kim SH, Lee A. Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer. J Pathol Transl Med. 2020 Jan;54(1):87-94. doi: 10.4132/jptm.2019.10.14. Epub 2019 Nov 13.
  • 10. Buck A, Schirrmeister H, Kühn T, Shen C, Kalker T, Kotzerke J, et al. FDG uptake in breast cancer: correlation with biological and clinical prognostic parameters. Eur J Nucl Med 2002; 29:1317–23.
  • 11. Zhang J, Jia Z, Zhou M, Ragaz J, Zhang YP, Wang BY, et al. The SUVmax for 18F-FDG correlates with molecular subtype and survival of previously untreated metastatic breast cancer. Clin Nucl Med 2013;38:256-62.
  • 12. Lakhani SR, Ellis IO, Schnitt SJ et al. eds. World Health Organization classification of tumours of the breast. 5th ed. Lyon: IARC Press, 2019.
  • 13. Rosen PP. Rosen’s Breast Pathology, 3rd edn. Philadelphia, PA, USA: Lippincott Williams & Wilkins, 2009.
  • 14. Wolff AC, Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018; 36: 2105-22.
  • 15. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al.; Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013
  • 16. Shannon J, Douglas-Jones AG, Dallimore NS. Conversion to core biopsy in preoperative diagnosis of breast lesions. Is it justified by the results? J Clin Pathol 2001;54:762–5.
  • 17. Pettine S, Place R, Babu S et al. Stereotactic breast biopsy is accurate, minimally invasive, and cost effective. Am J Surg 1996; 171: 474–476.
  • 18. Pijnappel RM, van Dalen A, Borel Rinkes IH et al. The diagnostic accuracy of core biopsy in palpable and non-palpable breast lesions. Eur J Radiol 1997; 24: 120–123.
  • 19. Verkooijen HM, Peeters PH, Buskens E et al. Diagnostic accuracy of large-core needle biopsy for nonpalpable breast disease: a meta-analysis. Br J Cancer 2000; 82: 1017–1021.
  • 20. Dillon MF, Hill AD, Quinn CM et al. The accuracy of ultrasound, stereotactic, and clinical core biopsies in the diagnosis of breast cancer, with an analysis of false negative cases. Ann Surg 2005; 242: 701–707.
  • 21. Usami S, Moriya T, Amari M et al. Reliability of prognostic factors in breast carcinoma determined by core needle biopsy. Jpn J Clin Oncol 2007; 37: 250–5.
  • 22. Alkabban FM, Ferguson T. Cancer, Breast. StatPearls Publishing Treasure Island (FL). 2019.
  • 23. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol 2014; 5: 412-424.
  • 24. Kunc M, Biernat W, Senkus-Konefka E. Estrogen receptor-negative progesterone receptor-positive breast cancer-"Nobody's land" or just an artifact? Cancer Treat Rev 2018;67:78-87.
  • 25. Damodaran D, Naidu BK, Varghese JC, Rajan P, Kuruvilla R, Kuruvilla S, et al.. A Prospective Study on Level of Concordance Between Core Needle Biopsy and Surgical Specimen for Assessing Oestrogen Receptor, Progesterone Receptor, and Her2/Neu Receptor Status in Carcinoma Breast and Its Implications on Treatment Decisions. Indian J Surg Oncol. 2020 Sep;11(3):446-450. doi: 10.1007/s13193-020-01146-y. Epub 2020 Jun 25.
  • 26. Asogan AB, Hong GS, Arni Prabhakaran SK. Concordance between core needle biopsy and surgical specimen for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status in breast cancer. Singapore Med J. 2017 Mar;58(3):145-149. doi: 10.11622/smedj.2016062. Epub 2016 Mar 31.
  • 27. Walter V, Fischer C, Deutsch TM, Ersing C, Nees J, Schütz F, et al. Estrogen, progesterone, and human epidermal growth factor receptor 2 discordance between primary and metastatic breast cancer. Breast Cancer Res Treat. 2020 Aug;183(1):137-144. doi: 10.1007/s10549-020-05746-8.
  • 28. Greer LT, Rosman M, Mylander WC, Hooke J, Kovatich A, Sawyer K, et al. Does breast tumor heterogeneity necessitate further immunohistochemical staining on surgical specimens? J Am Coll Surg. 2013 Feb;216(2):239-51.
  • 29. Meattini I, Bicchierai G, Saieva C, De Benedetto D, Desideri I, Becherini C, et al. Impact of molecular subtypes classification concordance between preoperative core needle biopsy and surgical specimen on early breast cancer management: Single-institution experience and review of published literature. Eur J Surg Oncol. 2017 Apr;43(4):642-648. doi: 10.1016/j.ejso.2016.10.025.
  • 30. Kondov B, Milenkovikj Z, Kondov G, et al. Presentation of the molecular subtypes of breast cancer detected by ımmunohistochemistry in surgically treated patients. Open Access Maced J Med Sci. 2018;6(6):961-967.
  • 31. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res 2009;7(1- 2):4-13.
Toplam 31 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Patoloji
Bölüm Araştırma Makalesi
Yazarlar

Yeliz Arman Karakaya 0000-0002-6669-9972

Sevda Yılmaz 0000-0002-1309-0805

Hande Karabaş Bu kişi benim 0000-0003-3064-3499

Yayımlanma Tarihi 1 Nisan 2021
Gönderilme Tarihi 24 Aralık 2020
Kabul Tarihi 20 Ocak 2021
Yayımlandığı Sayı Yıl 2021 Cilt: 14 Sayı: 2

Kaynak Göster

APA Arman Karakaya, Y., Yılmaz, S., & Karabaş, H. (2021). Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?. Pamukkale Medical Journal, 14(2), 416-427. https://doi.org/10.31362/patd.846610
AMA Arman Karakaya Y, Yılmaz S, Karabaş H. Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?. Pam Tıp Derg. Nisan 2021;14(2):416-427. doi:10.31362/patd.846610
Chicago Arman Karakaya, Yeliz, Sevda Yılmaz, ve Hande Karabaş. “Meme Kanseri Trucut iğne Biyopsi Ve Rezeksiyon Materyallerinde Yeni moleküler sınıflama, Tanı Ve Hormon reseptörlerinin Durumu Tutarlı mı?”. Pamukkale Medical Journal 14, sy. 2 (Nisan 2021): 416-27. https://doi.org/10.31362/patd.846610.
EndNote Arman Karakaya Y, Yılmaz S, Karabaş H (01 Nisan 2021) Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?. Pamukkale Medical Journal 14 2 416–427.
IEEE Y. Arman Karakaya, S. Yılmaz, ve H. Karabaş, “Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?”, Pam Tıp Derg, c. 14, sy. 2, ss. 416–427, 2021, doi: 10.31362/patd.846610.
ISNAD Arman Karakaya, Yeliz vd. “Meme Kanseri Trucut iğne Biyopsi Ve Rezeksiyon Materyallerinde Yeni moleküler sınıflama, Tanı Ve Hormon reseptörlerinin Durumu Tutarlı mı?”. Pamukkale Medical Journal 14/2 (Nisan 2021), 416-427. https://doi.org/10.31362/patd.846610.
JAMA Arman Karakaya Y, Yılmaz S, Karabaş H. Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?. Pam Tıp Derg. 2021;14:416–427.
MLA Arman Karakaya, Yeliz vd. “Meme Kanseri Trucut iğne Biyopsi Ve Rezeksiyon Materyallerinde Yeni moleküler sınıflama, Tanı Ve Hormon reseptörlerinin Durumu Tutarlı mı?”. Pamukkale Medical Journal, c. 14, sy. 2, 2021, ss. 416-27, doi:10.31362/patd.846610.
Vancouver Arman Karakaya Y, Yılmaz S, Karabaş H. Meme kanseri trucut iğne biyopsi ve rezeksiyon materyallerinde yeni moleküler sınıflama, tanı ve hormon reseptörlerinin durumu tutarlı mı?. Pam Tıp Derg. 2021;14(2):416-27.
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