Marmara Medical Journal
Transkript
Marmara Medical Journal
Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisi Editör Prof. Dr. Mithat Erenus Koordinatörler Seza Arbay, MA Dr. Vera Bulgurlu Editörler Kurulu Prof. Dr. Mehmet Ağırbaşlı Prof. Dr. Serpil Bilsel Prof. Dr. Safiye Çavdar Prof. Dr. Tolga Dağlı Prof. Dr. Haner Direskeneli Prof. Dr. Kaya Emerk Prof. Dr. Mithat Erenus Prof. Dr. Zeynep Eti Prof. Dr. RainerVV. Guillery Prof. Dr. Oya Gürbüz Prof. Dr. Hande Harmancı Prof. Dr. Hızır Kurtel Prof. Dr. Ayşe Özer Prof. Dr. Tülin Tanrıdağ Prof. Dr. Tufan Tarcan Prof. Dr. Cihangir Tetik Prof. Dr. Ferruh Şimşek Prof. Dr. Dr. Ayşegül Yağcı Prof. Dr. Berrak Yeğen Doç. Dr. İpek Akman Doç. Dr. Gül Başaran Doç. Dr. Hasan Batırel Doç. Dr. Nural Bekiroğlu Doç. Dr. Şule Çetinel Doç. Dr. Mustafa Çetiner Doç. Dr. Arzu Denizbaşı Doç. Dr. Gazanfer Ekinci Doç. Dr. Dilek Gogas Doç. Dr. Sibel Kalaça Doç. Dr. Atila Karaalp Doç. Dr. Bülent Karadağ Doç. Dr. Handan Kaya Doç. Dr. Gürsu Kıyan Doç. Dr. Şule Yavuz Asist. Dr. Asım Cingi Asist. Dr. Arzu Uzuner Marmara Medical Journal Marmara Üniversitesi T p Fakültesi Dergisi DERGİ HAKKINDA Marmara Medical Journal, Marmara Üniversitesi Tıp Fakültesi tarafından yayımlanan multidisipliner ulusal ve uluslararası tüm tıbbi kurum ve personele ulaşmayı hedefleyen bilimsel bir dergidir. Marmara Üniversitesi Tıp Fakültesi Dergisi, tıbbın her alanını içeren özgün klinik ve deneysel çalışmaları, ilginç olgu bildirimlerini, derlemeleri, davet edilmiş derlemeleri, Editöre mektupları, toplantı, haber ve duyuruları, klinik haberleri ve ilginç araştırmaların özetlerini , ayırıcı tanı, tanınız nedir başlıklı olgu sunumlarını, , ilginç, fotoğraflı soru-cevap yazıları (photo-quiz) ,toplantı, haber ve duyuruları, klinik haberleri ve tıp gündemini belirleyen güncel konuları yayınlar. Periyodu: Marmara Medical Journal -Marmara Üniversitesi Tıp Fakültesi Dergisi yılda 3 sayı olarak OCAK,MAYIS VE EKİM AYLARINDA yayınlanmaktadır. Yayına başlama tarihi:1988 2004 Yılından itibaren yanlızca elektronik olarak yayınlanmaktadır Yayın Dili: Türkçe, İngilizce eISSN: 1309-9469 Temel Hedef Kitlesi: Tıp alanında tüm branşlardaki hekimler, uzman ve öğretim üyeleri, tıp öğrencileri İndekslendiği dizinler: EMBASE - Excerpta Medica ,TUBITAK - Türkiye Bilimsel ve Teknik Araştırma Kurumu , Türk Sağlık Bilimleri İndeksi, Turk Medline,Türkiye Makaleler Bibliyografyası ,DOAJ (Directory of Open Access Journals) Makalelerin ortalama değerlendirme süresi: 8 haftadır Makale takibi -iletişim Seza Arbay Marmara Medical Journal (Marmara Üniversitesi Tıp Fakültesi Dergisi) Marmara Üniversitesi Tıp Fakültesi Dekanlığı, Tıbbiye cad No:.49 Haydarpaşa 34668, İSTANBUL Tel: +90 0 216 4144734 Faks: +90 O 216 4144731 e-posta: mmj@marmara.edu.tr Yayıncı Plexus BilişimTeknolojileri A.Ş. Tahran Caddesi. No:6/8, Kavaklıdere, Ankara Tel: +90 0 312 4272608 Faks: +90 0312 4272602 Yayın Hakları: Marmara Medical Journal ‘in basılı ve web ortamında yayınlanan yazı, resim, şekil, tablo ve uygulamalar yazılı izin alınmadan kısmen veya tamamen herhangi bir vasıtayla basılamaz. Bilimsel amaçlarla kaynak göstermek kaydıyla özetleme ve alıntı yapılabilir. www.marmaramedicaljournal.org Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisi YAZARLARA BİLGİ Marmara Medical Journal – Marmara Üniversitesi Tıp Fakültesi Dergisine ilginize teşekkür ederiz. Derginin elektronik ortamdaki yayınına erişim www.marmaramedicaljournal.org adresinden serbesttir. Marmara Medical Journal tıbbın klinik ve deneysel alanlarında özgün araştırmalar, olgu sunumları, derlemeler, davet edilmiş derlemeler, mektuplar, ilginç, fotoğraflı soru-cevap yazıları (photo-quiz), editöre mektup , toplantı, haber ve duyuruları, klinik haberleri ve ilginç araştırmaların özetlerini yayınlamaktadır. Yılda 3 sayı olarak Ocak, Mayıs ve Ekim aylarında yayınlanan Marmara Medical Journal hakemli ve multidisipliner bir dergidir.Gönderilen yazılar Türkçe veya İngilizce olabilir. Değerlendirme süreci Dergiye gönderilen yazılar, ilk olarak dergi standartları açısından incelenir. Derginin istediği forma uymayan yazılar, daha ileri bir incelemeye gerek görülmeksizin yazarlarına iade edilir. Zaman ve emek kaybına yol açılmaması için, yazarlar dergi kurallarını dikkatli incelemeleri önerilir. Dergi kurallarına uygunluğuna karar verilen yazılar Editörler Kurulu tarafından incelenir ve en az biri başka kurumdan olmak üzere iki ya da daha fazla hakeme gönderilir. Editör, Kurulu yazıyı reddetme ya da yazara(lara) ek değişiklikler için gönderme veya yazarları bilgilendirerek kısaltma yapmak hakkına sahiptir. Yazarlardan istenen değişiklik ve düzeltmeler yapılana kadar, yazılar yayın programına alınmamaktadır. Marmara Medical Journal gönderilen yazıları sadece online olarak http://marmaramedicaljournal.org/submit. adresinden kabul etmektedir. Yazıların bilimsel sorumluluğu yazarlara aittir. Marmara Medical Journal yazıların bilimsel sorumluluğunu kabul etmez. Makale yayına kabul edildiği takdirde Yayın Hakkı Devir Formu imzalanıp dergiye iletilmelidir. Gönderilen yazıların dergide yayınlanabilmesi için daha önce başka bir bilimsel yayın organında yayınlanmamış olması gerekir. Daha önce sözlü ya da poster olarak sunulmuş çalışmalar, yazının başlık sayfasında tarihi ve yeri ile birlikte belirtilmelidir. Yayınlanması için başvuruda bulunulan makalelerin, adı geçen tüm yazarlar tarafından onaylanmış olması ve çalışmanın başka bir yerde yayınlanmamış olması ya da yayınlanmak üzere değerlendirmede olmaması gerekmektedir. Yazının son halinin bütün yazarlar tarafından onaylandığı ve çalışmanın yürtüldüğü kurum sorumluları tarafından onaylandığı belirtilmelidir.Yazarlar tarafından imzalanarak onaylanan üst yazıda ayrıca tüm yazarların makale ile ilgili bilimsel katkı ve sorumlulukları yer almalı, çalışma ile ilgili herhangi bir mali ya da diğer çıkar çatışması var ise bildirilmelidir.( * ) ( * ) Orijinal araştırma makalesi veya vaka sunumu ile başvuran yazarlar için üst yazı örneği: "Marmara Medical Journal'de yayımlanmak üzere sunduğum (sunduğumuz) "…-" başlıklı makale, çalışmanın yapıldığı laboratuvar/kurum yetkilileri tarafından onaylanmıştır. Bu çalışma daha önce başka bir dergide yayımlanmamıştır (400 sözcük – ya da daha az – özet şekli hariç) veya yayınlanmak üzere başka bir dergide değerlendirmede bulunmamaktadır. Yazıların hazırlanması Derginin yayın dili İngilizce veya Türkçe’dir. Türkçe yazılarda Türk Dil Kurumu Türkçe Sözlüğü (http://tdk.org.tr) esas alınmalıdır. Anatomik terimlerin ve diğer tıp terimlerinin adları Latince olmalıdır. Gönderilen yazılar, yazım kuralları açısından Uluslararası Tıp Editörleri Komitesi tarafından hazırlanan “Biomedikal Dergilere Gönderilen Makalelerde Bulunması Gereken Standartlar “ a ( Uniform Requirements For Manuscripts Submittted to Biomedical Journals ) uygun olarak hazırlanmalıdır. (http://www. ulakbim.gov.tr /cabim/vt) Makale içinde kullanılan kısaltmalar Uluslararası kabul edilen şeklide olmalıdır (http..//www.journals.tubitak.gov.tr/kitap/ma www.marmaramedicaljournal.org knasyaz/) kaynağına başvurulabilir. Birimler, Ağırlıklar ve Ölçüler 11. Genel Konferansı'nda kabul edildiği şekilde Uluslararası Sistem (SI) ile uyumlu olmalıdır. Makaleler Word, WordPerfect, EPS, LaTeX, text, Postscript veya RTF formatında hazırlanmalı, şekil ve fotoğraflar ayrı dosyalar halinde TIFF, GIF, JPG, BMP, Postscript, veya EPS formatında kabul edilmektedir. Yazı kategorileri Yazının gönderildiği metin dosyasının içinde sırasıyla, Türkçe başlık, özet, anahtar sözcükler, İngilizce başlık, özet, İngilizce anahtar sözcükler, makalenin metini, kaynaklar, her sayfaya bir tablo olmak üzere tablolar ve son sayfada şekillerin (varsa) alt yazıları şeklinde olmalıdır. Metin dosyanızın içinde, yazar isimleri ve kurumlara ait bilgi, makalede kullanılan şekil ve resimler olmamalıdır. Özgün Araştırma Makaleleri Türkçe ve İngilizce özetler yazı başlığı ile birlikte verilmelidir. (i)özetler: Amaç (Objectives), Gereç ve Yöntem (Materials and Methods) ya da Hastalar ve Yöntemler (Patients and Methods), Bulgular (Results) ve Sonuç (Conclusion) bölümlerine ayrılmalı ve 200 sözcüğü geçmemelidir. (ii) Anahtar Sözcükler Index Medicus Medical Subject Headings (MeSH) ‘e uygun seçilmelidir. Yazının diğer bölümleri, (iii) Giriş, (iv) Gereç ve Yöntem / Hastalar ve Yöntemler, (v) Bulgular, (vi) Tartışma ve (vii) Kaynaklar'dır. Başlık sayfası dışında yazının hiçbir bölümünün ayrı sayfalarda başlatılması zorunluluğu yoktur. Maddi kaynak , çalışmayı destekleyen burslar, kuruluşlar, fonlar, metnin sonunda teşekkürler kısmında belirtilmelidir. Olgu sunumları İngilizce ve Türkçe özetleri kısa ve tek paragraflık olmalıdır. Olgu sunumu özetleri ağırlıklı olarak mutlaka olgu hakkında bilgileri içermektedir. Anahtar sözcüklerinden sonra giriş, olgu(lar) tartışma ve kaynaklar şeklinde düzenlenmelidir. Derleme yazıları İngilizce ve Türkçe başlık, İngilizce ve Türkçe özet ve İngilizce ve Türkçe anahtar kelimeler yer almalıdır. Kaynak sayısı 50 ile sınırlanması önerilmektedir. Kaynaklar Kaynaklar yazıda kullanılış sırasına göre numaralanmalıdır. Kaynaklarda verilen makale yazarlarının sayısı 6 dan fazla ise ilk 3 yazar belirtilmeli ve İngilizce kaynaklarda ilk 3 yazar isminden sonra “ et al.”, Türkçe kaynaklarda ise ilk 3 yazar isminden sonra “ ve ark. “ ibaresi kullanılmalıdır. Noktalamalara birden çok yazarlı bir çalışmayı tek yazar adıyla kısaltmamaya ve kaynak sayfalarının başlangıç ve bitimlerinin belirtilmesine dikkat edilmelidir. Kaynaklarda verilen dergi isimleri Index Medicus'a (http://www.ncbi.nim.nih.gov/sites/entrez/qu ery.fcgi?db=nlmcatalog) veya Ulakbim/Türk Tıp Dizini’ne uygun olarak kısaltılmalıdır. Makale: Tuna H, Avcı Ş, Tükenmez Ö, Kokino S. İnmeli olguların sublukse omuzlarında kas-sinir elektrik uyarımının etkinliği. Trakya Univ Tıp Fak Derg 2005;22:70-5. Kitap: Norman IJ, Redfern SJ, (editors). Mental health care for elderly people. New York: Churchill Livingstone, 1996. Kitaptan Bölüm: Phillips SJ, Whisnant JP Hypertension and stroke. In: Laragh JH, Brenner BM, editors. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York: Raven Pres, 1995:465-78. Kaynak web sitesi ise: Kaynak makalerdeki gibi istenilen bilgiler verildikten sonra erişim olarak web sitesi adresi ve erişim tarihi bildirilmelidir. Kaynak internet ortamında basılan bir dergi ise: Kaynak makaledeki gibi istenilen bilgiler verildikten sonra erişim olarak URL adresi ve erişim tarihi verilmelidir. Kongre Bildirileri: Bengtsson S, Solheim BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC, Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sep 6-10; Geneva, Switzerland. Amsterdam: North-Holland; 1992:1561-5. Tablo, şekil, grafik ve fotoğraf Tablo, şekil grafik ve fotoğraflar yazının içine yerleştirilmiş halde gönderilmemeli. Tablolar, her sayfaya bir tablo olmak üzere yazının gönderildiği dosya içinde olmalı ancak yazıya ait şekil, grafik ve fotografların her biri ayrı bir imaj dosyası (jpeg yada gif) olarak gönderilmelidir. www.marmaramedicaljournal.org Tablo başlıkları ve şekil altyazıları eksik bırakılmamalıdır. Şekillere ait açıklamalar yazının gönderildiği dosyanın en sonuna yazılmalıdır. Tablo, şekil ve grafiklerin numaralanarak yazı içinde yerleri belirtilmelidir. Tablolar yazı içindeki bilginin tekrarı olmamalıdır. Makale yazarlarının, makalede eğer daha önce yayınlanmış alıntı yazı, tablo, şekil, grafik, resim vb var ise yayın hakkı sahibi ve yazarlardan yazılı izin almaları ve makale üst yazısına ekleyerek dergiye ulaştırmaları gerekmektedir. Tablolar Metin içinde atıfta bulunulan sıraya göre romen rakkamı ile numaralanmalıdır. Her tablo ayrı bir sayfaya ve tablonun üst kısmına kısa ancak anlaşılır bir başlık verilerek hazırlanmalıdır. Başlık ve dipnot açıklayıcı olmalıdır. Sütun başlıkları kısa ve ölçüm değerleri parantez içinde verilmelidir. Bütün kısaltmalar ve semboller dipnotta açıklanmalıdır. Dipnotlarda şu semboller: (†‡¶§) ve P değerleri için ise *, **, *** kullanılmalıdır. SD veya SEM gibi istatistiksel değerler tablo veya şekildin altında not olarak belirtilmelidir. Grafik, fotoğraf ve çizimler ŞEKİL olarak adlandırılmalı, makalede geçtiği sıraya gore numaralanmalı ve açıklamaları şekil altına yazılmalıdır Şekil alt yazıları, ayrıca metinin son sayfasına da eklenmelidir. Büyütmeler, şekilde uzunluk birimi (bar çubuğu içinde) ile belirtilmelidir. Mikroskopik resimlerde büyütme oranı ve boyama tekniği açıklanmalıdır. Etik Marmara Medical Journal’a yayınlanması amacı ile gönderilen yazılar Helsinki Bildirgesi, İyi Klinik Uygulamalar Kılavuzu,İyi Laboratuar Uygulamaları Kılavuzu esaslarına uymalıdır. Gerek insanlar gerekse hayvanlar açısından etik koşullara uygun olmayan yazılar yayınlanmak üzere kabul edilemez. Marmara Medical Journal, insanlar üzerinde yapılan araştırmaların önceden Araştırma Etik Kurulu tarafından onayının alınması şartını arar. Yazarlardan, yazının detaylarını ve tarihini bildirecek şekilde imzalı bir beyan ile başvurmaları istenir. Çalışmalar deney hayvanı kullanımını içeriyorsa, hayvan bakımı ve kullanımında yapılan işlemler yazı içinde kısaca tanımlanmalıdır. Deney hayvanlarında özel derişimlerde ilaç kullanıldıysa, yazar bu derişimin kullanılma mantığını belirtmelidir. İnsanlar üzerinde yapılan deneysel çalışmaların sonuçlarını bildiren yazılarda, Kurumsal Etik Kurul onayı alındığını ve bu çalışmanın yapıldığı gönüllü ya da hastalara uygulanacak prosedürlerin özelliği tümüyle kendilerine anlatıldıktan sonra, onaylarının alındığını gösterir cümleler yer almalıdır. Yazarlar, bu tür bir çalışma söz konusu olduğunda, uluslararası alanda kabul edilen kılavuzlara ve TC. Sağlık Bakanlığı tarafından getirilen ve 28 Aralık 2008 tarih ve 27089 sayılı Resmi Gazete'de yayınlanan "Klinik araştırmaları Hakkında Yönetmelik" ve daha sonra yayınlanan 11 Mart 2010 tarihli resmi gazete ve 25518 sayılı “Klinik Araştırmalar Hakkında Yönetmelikte Değişiklik Yapıldığına Dair Yönetmelik” hükümlerine uyulduğunu belirtmeli ve kurumdan aldıkları Etik Komitesi onayını göndermelidir. Hayvanlar üzerinde yapılan çalışmalar için de gereken izin alınmalı; yazıda deneklere ağrı, acı ve rahatsızlık verilmemesi için neler yapıldığı açık bir şekilde belirtilmelidir. Hasta kimliğini tanıtacak fotoğraf kullanıldığında, hastanın yazılı onayı gönderilmelidir. Yazı takip ve sorularınız için iletişim: Seza Arbay Marmara Universitesi Tıp Fakültesi Dekanlığı, Tıbbiye Caddesi, No: 49, Haydarpaşa 34668, İstanbul Tel:+90 0 216 4144734 Faks:+90 0 216 4144731 e-posta: mmj@marmara.edu.tr www.marmaramedicaljournal.org İÇİNDEKİLER Orjinal Araştırma ASSESSMENT OF LEAD EXPOSURE AMONG THE WORKERS IN A STORAGE BATTERY FACTORY Nadi Bakırcı, Leyla Gedik Bakırcı…………………………………………….…66 THE COMPARISON OF THE EFFICACY OF CYPROTERONE ACETATE AND CASTRATION MONOTHERAPIES IN METASTATIC PROSTATE CANCER: A MULTICENTER STUDY OF TURKISH URO-ONCOLOGY GROUP Yaşar Beduk, Nural Bekiroğlu, Atif Akdaş, Haluk Özen, Tarık Esen, Cavit Can, Levent Türkeri……..75 THE EFFECT OF NITROUS OXIDE TO POSTOPERATIVE NAUSEA-VOMITING Hatice Türe, Arzu Takıl, Zeynep Eti, F. Yılmaz Göğüş…………………………………………….....…..…85 THE EFFECTS OF SPERM MORPHOLOGY AND MOTILITY ON THE OUTCOMES OF INTRACYTOPLASMIC SPERM INJECTION Vildan Karpuz, Aslı Göktürk, Meral Koyutürk……………………..……………………………….………..92 EFFECT OF CHEMOTHERAPY ON QUALITY OF LIFE IN PATIENTS WITH LYMPHOMA Esra Saatçi, Yüksel Koçak, Nafiz Bozdemir, Ersin Akpınar, Zeynep Kalaylıoğlu-Wheeler…………….98 THE IMPACT OF WOMEN’S HEALTH INITIATIVE STUDY ON INITIATION AND CONTINUATION OF HORMONE THERAPY IN A TERTIARY MENOPAUSE UNIT IN TURKEY Mithat Erenus, Meltem Uygur, Pınar Yörük, Fatih Durmuşoğlu…………………………………………104 Olgu Sunumu COLLOID CYST WITH SEPTUM PELLUCIDUM AGENESIS: A CASE REPORT AND REVIEW OF THE LITERATURE Deniz Konya, Arzu Gerçek, Serdar Özgen, M. Necmettin Pamir…………………………………………110 ANEURYSM OF THE POPLITEAL ARTERY: CASE REPORT Atike Tekeli, Selim Isbir, Koray Ak, Ali Civelek, Yasar Birkan, Taylan Adademir, Nazan Atalan Sinan Arsan……………………………………………………………………………………………...…….…114 ECTOPIC URETER DRAINING A POORLY FUNCTIONING RENAL MOIETY CAN BE MISSED BY IVP BUT NOT BY MRU Yusuf Temiz, Ferruh Şimşek, Salih Güran, Rengin Ahıskalı, Tufan Tarcan………...…………………..118 SEVERE PERIPHERAL NEUROPATHY SECONDARY TO VINCRISTIN THERAPY Ayşe Oytun Bayrak, Hande Türker, Ahmet Yılmaz, Musa Kazım Onar…………………………….……122 Derleme MITOCHONDRIAL DNA AND CANCER Cenk Aral, Ayşe Özer…………………………………...127 NATIONAL MEDICAL EDUCATION BOARD Mehmet Ali Gülpınar……………………...……..137 ARAŞTIRMA YAZISI BİR AKÜ FABRİKASINDA ÇALIŞAN İŞÇİLERDE KURŞUN MARUZİYETİNİN DEĞERLENDİRİLMESİ Nadi Bakırcı1, Leyla Gedik Bakırcı2 1 Marmara Üniveristesi, Tıp Fakültesi, Halk Sağlığı A.D. İstanbul, Türkiye 2Üsküdar Devlet Hastanesi, Biyokimya Laboratuvarı, İstanbul, Türkiye ÖZET Amaç: Bu araştırmada bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin sağlık etkilerini belirlemek ve işçileri kurşun zehirlenmesi açısından değerlendirmek amaçlanmıştır. Yöntem: İstanbul’da bir akü fabrikasında çalışan 56 erkek işçi araştırmaya katıldı. Bu kişilere yapılandırılmış bir anket uygulandı. Laboratuvar analizleri için uygun koşullarda kan örnekleri toplandı. Kurşun maruziyetinin göstergesi olarak kan kurşunu (K-Pb) düzeyleri indüktif eşleşmiş kütle spektrometrisi (ICP-MS) kullanılarak saptandı. Bulgular: Kurşun işlenen bölümlerde çalışan işçilerin K-Pb düzeyi ortancası 46mg/dL idi. Tüm çalışanların %68,5’inin, kurşunun işlendiği bölümlerde çalışanların %89,7’sinin K-Pb düzeyi zehirlenme sınırı olan 40mg/dL’nin üzerindeydi. İşçilerin %78,6’sı kurşun maruziyetinin ortaya çıkardığı temel klinik yakınmalardan en az birine sahipti. K-Pb düzeylerinin yaşa, maruziyet süresine ve sigara kullanımına göre dağılımında fark bulunmadı. Sonuç: Bu araştırmanın sonuçları akü işinde çalışan işçilerde kurşun zehirlenmesi riskinin çok yüksek olduğunu göstermektedir. Araştırmaya katılan işçilerde, daha önce benzer birçok çalışmada bildirilmiş K-Pb ortalamalarından daha yüksek bir ortalamanın olduğu görülmektedir. Elde edilen bu sonuçlarda yoğun kurşun maruziyetinin etkisinin yanında işçilerin izleminin iyi yapılmamasının da etkisi olabilir. Anahtar sözcükler: Kurşun zehirlenmesi, Akü işçileri, İşçi sağlığı, Çevresel maruziyet ASSESSMENT OF LEAD EXPOSURE AMONG THE WORKERS IN A STORAGE BATTERY FACTORY ABSTRACT Objective: In this study we aimed to determine the health effects of lead exposure and assess the lead intoxication in battery production plant workers. Material and Methods: Fifty-six workers accepted to participate in the study. A structured questionnaire was given to evaluate the symptoms, and blood samples were collected for laboratory analyses. Blood lead concentration (B-Pb) was studied by ICP-MS method to assess the lead exposure. Results: The median of B-Pb concentration was 46mg/dL among the workers in lead production departments. Sixty nine percent of all the workers and 89,7% of the workers in lead production departments had lead intoxication. Seventy nine percent of the workers had at least one symptom related to lead exposure. There was no relationship between age, exposure time and smoking. Conclusion: In conclusion, the results indicated that the workers have a high lead intoxication risk in battery production plants. In this study, extremely high levels of B-Pb were recorded. These levels were higher than the levels that have been reported in similar studies. This significantly high intoxication rate at the battery factory can be explained by the inadequacy of the environmental measures and lack of periodical controls and treatment of the workers. Key words: Lead intoxication, Storage battery workers, Occupational health, Environmental exposure İletişim Bilgileri: Dr.Nadi Bakırcı Marmara Üniveristesi, Halk Sağlığı, İstanbul, Türkiye e-mail: nbakirci@marmara.edu.tr Marmara Medical Journal 2007;20(2);66-74 66 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi Kurşunun mesleksel ve çevresel maruz kalımı bir halk sağlığı sorunu olarak önemini korumaktadır.Erişkinlerdeki kurşun zehirlenmesinin %95’inin mesleksel kökeni olduğu gösterilmiştir. Kurşunun sanayide en önemli kullanım alanı akü üretimidir. Bunun dışında kimyasal maddeler ve pigmentlerde, boyalarda, seramik yapımında, kablo izolasyonunda, hadde ve diğer ürünlerde, alaşımlarda ve benzin katkısı olarak kuşun kullanılmaktadır. işlemine tabi tutulur. Antimon ile dayanıklılığı arttırılan kurşunun dökümü yapılır ve ızgaralar elde edilir. Aynı zamanda kurşundan elde edilen kurşun oksit sülyen ve sülfirik asit ile karıştırılarak akü hamuru elde edilir. Izgaralar bu hamurla sıvanır ve plakalar elde edilir. Bu şekilde hazırlanan plakalar kurutulur ve formasyon şarjı uygulanır. Hazırlanmış kutulara plaklar yerleştirilir ve şarj edilir. Bütün bu süreçlerde yoğun bir kurşun maruziyeti söz konusudur. Özellikle kurşunun işlendiği aşamalarda maruz kalım en yüksek düzeylerine ulaşır. Kurşunun çok çeşitli sağlık etkisi olduğu gösterilmiştir. Özellikle hematolojik sistem, merkezi sinir sistemi, böbrekler, karaciğer, gibi birçok sistemi ve organı etkilemekte; üreme sağlığı ile ilgili ciddi sorunlar doğurmaktadır 1-8. Endüstride kurşun maruziyetini ve sağlık etkilerini izlemek için düzenli olarak kan kurşun düzeylerinin incelenmesi gereklidir. Ne yazık ki, Türkiye’de bu izlem çok sınırlı düzeyde yürütülmektedir. Akü üretiminin önemli bir kısmında kurşuna maruz kalım vardır. Şekil 1’de akü imalatının temel aşamaları izlenebilir. Temelde üretim süreci iki koldan işler. Bir yandan kurşun işlenerek plaka haline gitirilirken diğer yandan plakaların monte edileceği kutu imalatı yapılır. İlkin ham kurşun ergitme Bu araştırmada amaç kurşunun en yoğun kullanıldığı ve çalışanların kurşundan en fazla etkilendiği akü üretiminde kurşun taraması yapmak ve bu işçilerdeki kurşun zehirlenmesini saptamaktır. Etkilenmenin olduğu işçilerin tedavilerini sağlamak için de planlama yapılmıştır. GİRİŞ Şekil 1: Akü imalatında temel adımlar 67 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi ile (Ultra Scientific ICP-082) 1µg/dL, 2 µg/dL, 3 µg/dL, 5 µg/dL, 10 µg/dL, 20 µg/dL, 30 µg/dL, 50 µg/dL, 100 µg/dL konsantrasyonlarında çalışma standartları hazırlanmış, daha sonra, her bir standarttan 0,5ml alınmış ve üzerine %0,01 EDTA (Merck 8421) içeren %25’lik TMAH (Fluka 87729) çözeltisinden 0,5 ml ilave edilmiştir. Karıştırılarak 1 saat oda ısısında bekletilmiştir. Her birinin üzerine 100mcl iç standart (Ultra Scientific ICP-058) ilave edilmiş ve distile suyla 5ml ye tamamlanmıştır. Girdaplanarak iyice karışmaları sağlanmıştır. ICP-MS cihazı çalışma parametrelerine göre ayarlanmış ve önce standartlar ardından örnekler sırasıyla cihaza yüklenmiştir. Her bir standart ve örnek üç kez okutularak çalışılmıştır. Her 10 örnek arasında çeşitli konsantrasyondaki standartlar tekrar okutulmuştur. GEREÇ-YÖNTEM Araştırma grubu: İstanbul’da bir akü fabrikasında çalışan 56 erkek işçi araştırmaya katılmıştır. Araştırmaya başlamadan üniversite etik kurulundan onay alınmış, fabrikadaki işçilere araştırmanın amaçları anlatılmış ve kabul edenler araştırmaya katılmıştır. Araştırmaya katılmayı reddeden olmamış ancak iki kişide kan kurşun analizi yapılamamıştır. Anket: Araştırmaya katılacak kişilere kurşun maruziyetini değerlendirmek için yapılandırılmış bir anket uygulanmıştır. Ankette kişilerin çalıştıkları bölüm, kaç yıldır çalıştıkları, temizlik alışkanlıkları, kronik hastalıklarının varlığı, vitamin dahil herhangi bir ilaç kullanımları, sigara ve alkol alışkanlıkları ve kurşuna maruz kalımla oluşabilecek yakınmaları sorgulanmıştır. İstatistiksel analizler: Kan kurşun düzeyi analizi: İşçilerde K-Pb düzeyleri 40 µg/dL altında ve üstünde olmasına göre iki gruba ayrılmış ve 40 µg/dL ‘in üstü kurşun toksikasyonu olarak kabul edilmiştir. İşçilerin çalıştıkları 9 farklı bölüm “yönetim”, “kutu imalatı” ve “kurşun işlenen bölümler” şeklinde 3 grupta toplanarak analiz edilmiştir. Toksikasyona göre gruplar arasındaki yüzdelerin farklılığı Ki-kare testi ile kan kurşun değerlerinin ortalamalarındaki farklılık Kruskal Wallis testi ile analiz edilmiştir. Kurşun maruziyeti kan kurşun düzeyi ile değerlendirilmiştir. Kan örnekleri, kurşun analizi için önerilen yöntemler kullanılarak toplanmıştır. İşçilerden EDTAlı ve heparinli venöz kan örnekleri alınmıştır. Kan alım işlemi bu iş için ayrılmış ve temizlenmiş bir odada, deneyimli hekimlerce yapılmıştır. Önce işçilerin kolları sabun ve suyla yıkatılmış ve kurutmaları için tek kullanımlık havlular kullanılmıştır. Daha sonra, kan alınacak yüzey önce povidon iyot sonra alkolle temizlenmiş, kan alım işlemi için plastik vakumlu tüpler kullanılmıştır. Gerek bu aşamada gerekse analizler sırasında kullanılan tüm kurşundan arındırılmış cam malzemler ve pipet uçları %20’lik nitrik asitte 24 saat bekletilmiş ve deiyonize suyla durulandıktan sonra 50 oC lik etüvde kurutulmuştur. Kurşun analizinin yapılmasına kadar EDTAlı kanlar –20 oC’de bekletilmiştir. Tüm sonuçlarda istatistiksel anlamlılık olarak p<0.05 kabul edilmiştir. BULGULAR Araştırmaya katılan işçilerin tümü erkekti. %25’i 25 yaşın altında idi ve büyük oranda (%43) bir yıldan daha az süredir kurşuna maruz kalmışlardı. İşçilerin %61’i sigara içmekte idi. Daha önce kurşun zehirlenmesi geçirdiğini söyleyen 4 işçi (%7) vardı. (Tablo I) Kan kurşun analizleri atomik kütle spektrometrisi çalışma prensiplerine dayalı olarak çalışan CP-MS (Inductively Coupled Plasma Mass Spectrometry) cihazıyla yapılmıştır9. Önce kurşun standart solüsyonu Kan kurşun düzeylerinin 40 µg/dL’nin altında ve üstünde olmasına göre işçilerin dağılımları Tablo II’de sunulmuştur. Yaşa, sigara içme durumuna ve kurşuna maruz kalam süresine 68 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi göre kan kurşun düzeylerinin değişmediği görüldü. Daha önce kurşun zehirlenmesi geçirdiğini bildiren 4 işçide zehirlenmenin devam ettiği gösterilmiştir. Kurşunun işlendiği bölümlerde çalışanların %89,7’sinde K-Pb düzeyi 40 µg/dL’nin üstünde saptanmışken, kutu yapımı ve yönetimde çalışanların tümünde K-Pb bu düzeyin altında ölçülmüştür (p<0,001). Bu üç bölümde çalışanların K-Pb ortalamalarının da farklı olduğu görülmüştür. Kurşun işlenen bölümlerde 46µg/dL, kutu yapımında 29µg/dL ve yönetimde çalışanlarda 17 µg/dL olmak üzere ortanca K-Pb düzeyleri gözlenmiştir (Tablo III). Şekil 2’de tüm bölümlerdeki görülmektedir. ortalama düzeyler Tablo IV’te işçilerdeki yakınmaların sıklığı ve K-Pb düzeylerine göre dağlımları görülmektedir. En sık bildirilen yakınmalar halsizlik (%46), kas-eklem ağrısı (%38), baş ağrısı (%34), sinirlilik (%27), iştahsızlık (%21) ve karın ağrısı (%21) olmuştur. İşçilerin %78,6’sında kurşun maruziyetinin ortaya çıkardığı temel klinik yakınmalardan en az biri bulunmaktaydı. 40 µg/dL’nin üstünde K-Pb olanlarda karın ağrısı sıklığı daha yüksekti (%29.7’ye karşın %6.3) (p<0.05). Tablo I: Araştırmaya katılan işçilerin bazı özelliklerine göre dağılımı Sayı (n=56) % Yaş 25 altı 25-29 30-34 35-39 40 ve üstü Sigara İçiyor İçmiyor Çalıştığı bölüm Oksit Izgara Sıvama Plaka Formasyon Montaj Kutu yapımı (enjeksiyon) Tüm bölümler Yönetim Kurşuna maruz kalma süresi 1 yılın altında 1-4 yıl 5 yıl ve üzeri Daha önce kuşun zehirlenmesi geçirenler 69 14 12 10 6 14 25,0 21,4 17,9 10,7 25,0 34 22 60,7 39,3 2 7 6 4 7 12 6 7 5 3,6 12,5 10,7 7,1 12,5 21,4 10,7 12,5 8,9 24 16 16 4 42,9 28,6 28,6 7,1 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi Tablo II: İşçilerin K-Pb düzeylerine bağlı olarak bazı özelliklerine göre dağılımı K-Pb düzeyi (µg/dL) < 40 > 40 (n=17) (n=37) 17 (31,5) 37 (68,5) İstatistiksel önemlilik Tüm çalışanlar Yaş 25 altı 5 (35,7) 9 (64,3) 25-29 1 (9,1) 10 (90,9) 30-34 6 (60,0) 4 (40,0) p=0,08* 35-39 2 (33,3) 4 (66,7) 40 ve üstü 3 (23,1) 10 (76,9) Sigara, n(%) İçiyor 10 (31,3) 22 (68,8) p=0,597 İçmiyor 7 (31,8) 15 (68,2) Kurşuna maruz kalma süresi, n(%) 1 yılın altında 7 (29,2) 17 (70,8) 1-4 yıl 4 (26,7) 11 (73,3) p=0,695 5 yıl ve üzeri 6 (40,0) 9 (60,0) Çalıştığı bölüm, n(%) 2 (100,0) Oksit 6 (85,7) 1 (14,3) Izgara 5 (100,0) Sıvama 4 (100,0) Plaka Test 7 (100,0) Formasyon uygulanmadı 9 (75,0) 3 (25,0) Montaj 4 (66,7) 2 (33,3) Tüm bölümlerde çalışma 6 (100,0) Kutu yapımı (enjeksiyon) 5 (100,0) Yönetim Çalıştığı bölüm-grup, n (%) 6 (10,8) 37 (89,7) Kurşun işlenen bölümler 6 (100,0) p<0,001** Kutu yapımı (enjeksiyon) Yönetim 5 (100,0) Daha önce kuşun zehirlenmesi Var 4 (100,0) p=0,21 Yok 17 (34,0) 33 (66,0) * ”35-39” ve “40 ve üstü” gruplar birleştirilerek test uygulandı ** Kutu imalatında ve yönetimde çalışanlar birleştirilerek Fisher Exact test uygulandı 70 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi Tablo III: İşçilerin çalıştıkları bölümlere göre kan kurşun düzeylerinin ortancaları* Çalıştığı bölüm Ortanca K-Pb(µg) Kurşun işlenen bölümler 25.-75. yüzdelik 46,0 42,1-56,6 48,5 49,3 48,7 49,7 52,2 46,8 50,9 40,3-56,6 42,7-68,5 47,3-69,8 43,1-53,6 41,9-61,7 35,7-56,5 34,0-53,4 Kutu yapımı (enjeksiyon) 28,9 17,0-32,5 Yönetim 17,1 14,1-25,5 Oksit Izgara Sıvama Plaka Formasyon Montaj Tüm bölümlerde çalışma * Kruskal Wallis Test Ki-Kare=24,8; p<0,0001 Tablo IV: İşçilerin K-Pb düzeylerine bağlı olarak bildirdikleri semptomlara göre dağılımı Toplam K-Pb düzeyi (mcg/dL) 40 alt 40 ve üstü Say Yüzde Semptomlar (n=17) (n=37) (n=56)a Halsizlik 26 46,4 5 (29,4) 20 (54,1) Kas eklem ağrısı 21 37,5 4 (23,5) 17 (45,9) Baş ağrısı 19 33,9 5 (29,4) 8 (21,6) Sinirlilik 15 26,8 5 (29,5) 8 (21,6) İştahsızlık 12 21,4 3 (17,6) 9 (24,3) Karın ağrısı 12 21,4 1 (5,9) 11 (29,7) b Hazımsılık 4 7,1 4 (10,8) Kabızlık 2 3,6 1 (5,9) 1 (2,7) a b Kan kurşun düzeyi ölçülmeyen iki işçi eklenmiştir p<0,05 71 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi Şekil 2: İşçilerin çalıştıkları bölümlere göre kan kurşun düzeyleri (µg/dL) alanlarda çalışan ancak kurşunun işlenmediği bölümlerde çalışan işçilerde (kutu yapımı) yönetimdeki işçilerden daha yüksek bir maruziyet düzeyine sahip olduğu söylenebilir. Kurşunun işlendiği bölümdeki işçiler ise fabrikanın en yüksek kurşun düzeylerinde çalışmaktadırlar. İşletmelerde bu yüksek riskli bölümlerin saptanması ve öncelikli olarak buradaki işçilerin izlenmesinin önemi bu sonuçlarla tekrar vurgulanmaktadır. TARTIŞMA Kurşun ile çalışan akü işçilerinde daha önce birçok araştırmada yüksek oranda kurşun zehirlenmesi bildirilmiştir ve tanı konan kurşun zehirlenmesi olgularının büyük kısmı akü fabrikalarında çalışan işçilerdir10-12. Bu çalışmada da işçilerde çok yüksek kan kurşun düzeyleri gözlenmiştir. Özellikle kuruşunun işlendiği bölümlerde toksikasyon oranı %90’a ulaşmaktadır. Bu durum büyük bir olasılıkla daha önce periyodik kan kurşun düzeylerinin ölçümünün yapılmamasından kaynaklanmaktadır. Daha önce kurşun toksikasyonu tanısı almış 4 işçinin halen yüksek düzeyde K-Pb ye sahip olmaları tanı ve tedavi sistemlerinin çalışmadığını göstemektedir. Bu çalışmada, maruz kalım süresi ile K-Pb düzeyleri arasında bir ilişki belirlenememiştir. İşçi Sağlığı İş Güvenliği Enstitüsü’nün (İSGÜM) yaptığı kan kurşunu taramalarında uzun yıllar boyunca kurşuna maruz kalanlarda K-Pb düzeylerinin azaldığı görülmüştür13. Yapılan başka araştırmalarda yaş ve maruziyet süresi K-Pb düzeyini artıran bir etken olarak bulunmamıştır14,15. Maruz kalım süresinin uzamasına bağlı olarak artışın görülmemesi K-Pb düzeyinin son dönemdeki kurşuna maruziyetin süre ve şiddetiyle değişebilir olması, kişisel metabolizma farklılıkları ve uzun süreli kurşun maruziyetinin kurşun kinetiği üzerindeki etkisi ile açıklanabilir. Aynı fabrikada kurşunun işlendiği süreçlerde çalışan işçiler bu süreçlerde çalışmayanlara göre daha fazla zehirlenme riski altındadırlar. Bu araştırmada kurşunun çevresel maruziyeti ölçümü yapılmamasına karşın fabrikada çalışan işçilerin farklı düzeylerde kurşuna maruz kalmış olduğu öngörülebilir. K-Pb düzeyleri maruziyetin iyi bir göstergesidir ve yönetim görevi olan işçilerde en düşük düzeyde saptanmıştır. Toksikasyon sınırının altında olmasına karşın üretimin yapıldığı Kurşunla çalışan işçilerin sigara içmesi alınan kurşun dozunun artışına neden olabilir. 72 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi Çalışma ortamındaki kurşun içilen sigara yoluyla alınır. Bu nedenle işçilerin sigara içmeleri yasaklanmaktadır. Diğer yandan sigara dumanı zaten bir miktar kurşun içerir ve bu yollada kurşun alımı olasıdır. Üç ülkeyi kapsayan geniş bir çalışmada filtreli sigaralardaki kurşun düzeyi 2,4 µg/gr olarak bildirilmiştir. Ayrıca günde 20 sigara içenlerin 1-5 µg/gr kurşun inhale ettiklerine dikkat çekilmiştir2. Çalışmamızda sigara içenlerde ve içmeyenlerde K-Pb düzeylerinin değişmediği görülmektedir. K-Pb düzeyinin yükselmesinde mesleksel maruz kalıma göre sigara içmenin payının daha düşük olması beklenir. Çok yüksek düzeyde mesleksel maruz kalım sigaranın etkisini gölgelemiş olabilir. kullanılan yöntemdir. Kesin intoksikasyon tanısı konması için kan kurşun düzeyi yüksek olan işçiler, ileri analiz amacıyla Meslek Hastalıkları Hastanesine sevk edilmiştir. Sonuç olarak: K-Pb düzeylerinin akü işi yapılan fabrikalarda özellikle kurşunun işlendiği bölümlerde çalışanlarda çok yüksek düzeylere ulaşabileceğini göstermektedir. Bu sonuç, işçilerde düzenli K-Pb taramalarının yapılarak toksikasyonların saptanmasının ve tedavi edilmelerinin önemini ortaya koymaktadır. Kurşun toksikasyonu olan işçilerin uygun tedavi almaları için yönlendirmeleri yapılmıştır. Fabrikada alınacak gerekli önlemler işverene sunulmuştur. Teşekkür İşçilerde kurşun maruziyetinin ortaya çıkarabileceği en temel klinik yakınmalar değerlendirilmiştir. İşçilerde halsizlik, kaseklem ağrısı, baş ağrısı, sinirlilik, iştahsızlık ve karın ağrısı en sık görülen yakınmalar olarak saptanmıştır. Bu yakınmalar büyük ölçüde etkilenmenin başladığı ilk dönemlerden itibaren ortaya çıkabilmektedir16. Bu durum işçilerin aralıklı sağlık kontrollerinin yapılırken bu yakınmaların sorgulanmasının önemini bir kez daha ortaya koymaktadır. Saha çalışmasındaki desteği için İstanbul Meslek Hastalıkları Hastanesi’nden Dr.Fatih Hemşioğlu’na ve kan kurşun analizlerini yapan Çevre Endüstriyel Analiz Laboratuvarı çalışanlarına teşekkür ederiz. KAYNAKLAR 1. MD Sanborn, A Abelsohn, M Campbell, E Weir. Identifying and managing adverse environmental health effects: 3. Lead exposure. CMAJ 2002;166(10):1287-92 2. WHO. Environmental Health Criteria 165, Inorganic Lead. Geneva, 1995 3. Goyer AR, Lead Toxicity: Corrent Concerns. Environ Health Perspectives 1993;100:177-87 4. Bernard BP, Bechara CE. Environmental lead exposure and the kidney. Clin Toxicol 1988;26:1-34 5. Goldstein GV. Lead poisoning and brain cell function. Environ Health Perspect 1990;89:91-4 6. Pagliuca A, Mutti GT, Baldwin D, Lestas AN, Wallis RM. Lead poisoning clinical, biochemical, and hematological aspects of a recent outbreak. J Clin Pathol 1990;43:277-81 7. Lanphear BP, Hornung R, Khoury J, ve ark. Low-level environmental lead exposure and children's intellectual function: An international pooled analysis. Environmental Health Perspectives 2005;113(7):894-9 8. Ning T; Zi Q Adverse reproductive effects in female workers of lead battery plants. Int J Occup Med Envir Health 2003;16(4):356-61 9. Adams A, Gijbels R. Mass spectrometry. Anal Chem 1988;60:70-4 10. Tonguç E, Paya D. Mesleki Anorganik Kurşun Zehirlenmesi. SSK 8. Tıp Kongresi. Antalya 1977. SSK Genel Müdürlüğü Yayınları N0:316 11. Sirer H, Abir Ş, Gören T, Yasav G. Bir yılda Marmara Bölgesinden Gelen Kronik Kurşun İntoksikasyonu olguları. 1. Ulusal İşçi Sağlığı Kongresi. 1978 İstanbul. Istanbul Tabip Odası Yayını. 1978, 258-263 Yakınmaların ortaya çıkmasında K-Pb’nin artışı önemli bir faktör olarak öngörülmekle birlikte K-Pb’si düşük düzeylerde olan kurşun işçilerinde de ağır yakınmalara rastlanabilmektedir. İSGÜM’ün yaptığı taramada yakınmaların daha fazla sıklıkla KPb düzeylerinin düşük olduğu grupta olduğu gösterilmiş ve bu durum yakınmaların subjektif ve non-spesifik olmasına 13 bağlanmıştır . Yaptığımız araştırmada, KPb’nin 40 µg/dL’nin üstünde olan grupta kabızlık dışında tüm yakınmalar daha sık olarak bulunmuştur. Karın ağrısı yakınması olan işçilerin %91,7’sinde K-Pb 40 µg/dL’nin üzerindedir (p<0,05). Kurşun maruziyetinin değerlendirilmesi için sadece K-Pb analizlerinin yapılması bu araştırmanın bir limitasyonu olarak düşünülebilir. Ancak bu, maruziyetin biyolojik olarak izlenmesi için en sık 73 Marmara Medical Journal 2007;20(2);66-74 Nadi Bakırcı, ark. Bir akü fabrikasında çalışan işçilerde kurşun maruziyetinin değerlendirilmesi 12. Yeşilleten N, Baykal Y, Öztürk A, Yasav G, Telman N. Endüstimizin Önemli Bir Problemi: Kurşun İntoksikaysyonları (1973-1983). SSK Tıp Bilteni 1984;4(2):51-69 13. Çalışma ve Sosyal Güvenlik Bakanlığı İşçi Sağlığı ve İş Güvenliği Enstitüsü. Akü işçilerinde kurşun zehirlenmesi taraması. İSGÜM Basımevi. Ankara,1990 14. Ersoy Ö. Kurşunlu akümülatör üreten işyerlerinde kuşuna maruz kalmanın incelenmesi. Mar Üniv Ecz Der 1985;1(1-2):35-49 15. Lormphongs S, Miyashita K, Morioka I, Chaikittiporn C, Miyai N, Yamamoto H. Lead exposure and blood lead level of workers in a battery manufacturing plant in Thailand. Ind Health 2003 Oct;41(4):348-53. 16. Tonguç E. Meslek hastalıkları klavuzu. TTB Yayınları., Ankara,1992 74 ORIGINAL RESEARCH THE COMPARISON OF THE EFFICACY OF CYPROTERONE ACETATE AND CASTRATION MONOTHERAPIES IN METASTATIC PROSTATE CANCER: A MULTICENTER STUDY OF A TURKISH URO-ONCOLOGY GROUP Yasar Beduk1, Nural Bekiroğlu2, Atıf Aktaş3, Haluk Özen4, Tarık Esen5, Cavit Can6, Levent Türkeri3 1 Department of Urology,School of Medicine,Ankara University,Ankara,Türkiye 2Department of Biostatistics, School of Medicine,Marmara University, Istanbul, Türkiye 3Department of Urology, School of Medicine, Marmara University, İstanbul, Türkiye 4Department of Urology, School of Medicine, Hacettepe University, Ankara, Türkiye 5Department of Urology, School of Medicine, İstanbul University, İstanbul, Türkiye 6Department of Urology, School of Medicine, Osmangazi University, Bursa, Türkiye ABSTRACT Objective: To detect the therapeutic efficacy of CPA and to compare it with surgical or medical castration in advanced prostate cancer Patients and Methods: Patients from 19 Urology Centers with prostate adenocarcinoma of stages T14N+MX or T1-4NXM+ were enrolled. A total of 120 patients were randomized to receive CPA 3X100mg/d(Group 1) versus medical or surgical castration(Group 2).The primary endpoints for this trial were overall and disease-spesific survival.Progression-free survival(PSA progression time) and testosterone decrease rate were assessed as secondary endpoints.Progression-free survival probabilities were calculated by the Kaplan-Meier method and comparison of survival probabilities was performed by the Logrank test. Results: The median PSA values were 42ng/dl in both groups at initiation and decreased to 3.0 and 2.1 respectively in 3 months(p>0.05).Castrate testosterone levels were reached in two groups after 3 months therapy( 9% and 6.7% of initial values respectively;p>0.05).The data is immature to assess the survival durations,but in median follow-up of 24 months,no difference in regard to PSA-progression was detected in the two groups(p=0.616). Conclusion: This randomized study of CPA and castration in patients with metastatic prostate cancer has not so far revealed any significant differences in progression-free survival.The initial efficacy and tolerability of monotherapy encourages us to comment that this therapy is safe and acceptable. Keywords: Prostate cancer,Cyproterone acetate,Castration,PSA-progression,Survival METASTATİK PROSTAT KANSERİNDE CYPROTERONE ACETATE VE KASTRASYON MONOTERAPİLERİNİN ETKİNLİĞİNİN KARŞILAŞTIRMASI: ÇOK MERKEZLİ BİR TÜRK ÜRO-ONKOLOJİ GRUBU ÇALIŞMASI ÖZET Amaç: İlerlemiş prostat kanserinde tibbi veya cerrahi kastrasyon ile CPA’yi karşılatırmak ve CPA’nin terapötik etkisini ortaya koymak. Gereç ve Yöntem: Ondokuz Üroloji Merkezi’ne başvuran T1-4N+MX veya T1-4NXM+ evreli prostat adenokanserli hastalar çalışmaya alınmıştır. Toplam 120 hasta, CPA 3X100mg/gün (Grup1) ve tıbbi veya cerrahi kastarasyon (Grup 2) gruplarına rastgele dağıtılmışlardır. Bu denemenin birincil son noktaları genel ve hastalığa-özel sağkalım olasılıklarıdır. Progresyonsuz sağkalım (PSA progresyon zamanı) ve testesteron düşüş hızı ikincil son noktalar olarak kabul edilmiştir.Progresyonsuz sağkalım olasılıkları Kaplan-Meier metoduyla hesaplanmış ve Logrank testiyle de sağkalım olasılıkları karşılaştırılmıştır. Corresponding author: Prof. Yasar Beduk, M.D Ankara University, Urology, Ankara, Türkiye e-mail: yasarbeduk@superonline.com Marmara Medical Journal 2007;20(2);75-84 75 Marmara Medical Journal 2007;20(2);75-84 Yasar Bedük, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of Turkish uro-oncology group Bulgular: Başlangıçta her iki grupta da PSA ortanca(medyan) değerleri 42ng/dl bulunmuş ve 3 ayda Grup1’de 3.0 ‘e Grup2’de de 2.1’e düşmüştür (p>0.05). Her iki grupta da 3 aylık bir tedavi sonrasındaki testesteron seviyeleri başlangıçtaki değerlerin Grup1’de % 9’una Grup2’de %6.7’sine ulaşmıştır (p>0.05).Her ne kadar veriler sağkalım süreleri için tam olmasa bile, ortanca 24 aylık izlem süresinde PSAprogresyonu için iki grup sağkalımlarında bir fark bulunmamıştır (p=0.616). Sonuç: Yaptığımız bu randomize çalışma, CPA ve kastrasyon tedavisi alan prostat kanserli hastalarda progresyonsuz sağkalım bakımından 24 aylık izlem zarfında herhangi bir anlamlı faklılık ortaya koymamıştır. Monoterapinin başlangıçtaki etkinliği ve tolerabl olması bu terapinin kabul edilebilir ve güvenilir bir tedavi olduğu yorumlarında bizi cesaretlendirmektedir. Anahtar Kelimeler: Prostat kanseri,CPA,Kastrasyon,PSA-progresyon,Sağkalım This trial aimed to detect the therapeutic efficacy of CPA and compare it with surgical or medical castration in a group of patients with locally advanced and/or metastatic prostate cancer with a relatively favorable prognosis.The primary end-point of this study was the mean overall and disease-spesific survival times in the treatment groups. Secondary end-points were the comparison of the treatment arms with respect toprostate specific antigen (PSA)-progression and castrate testosterone levels. INTRODUCTION Prostate cancer is an androgene hormoneresponsive tumour and is generally controlled by removal of the androgenic stimulus 1,2. Surgical castration has been considered the “gold standard” treatment for metastatic prostate cancer 3 and most studies concerning other hormonal therapies for metastatic disease have used bilateral orchidectomy as the comparator.On the other hand,studies demonstrate that luteinizing hormone releasing hormone (LHRH) agonists such as goserelin are as effective as orchidectomy 4,5. PATIENTS AND METHODS This was a multicenter, prospective, randomised study conducted at 19 Urology Centers in Turkey. The aim of the trial was to compare the efficacy of CPA with surgical or medical castration in metastatic prostate adenocarcinoma. In the 1980’s, maximum androgene blockade (MAB) gained a wide acceptance among urologists for the treatment of metastatic prostate cancer.However,after the report of a meta-analysis of 27 of these studies which indicated only a small difference in overall survival at 5 years in favor of MAB 6, enthusiasm subsided. As there is clear evidence of the limited clinical value of MAB in the treatment of metastatic prostate cancer today; attention is again focused on monotherapy. If this is as effective as MAB, quality of life and cost-effectiveness would indicate monotherapy.Another recent issue is the use of oral antiandrogens such as monotherapy in the treatment of metastatic prostate cancer.Until recently, antiandrogens were only used as a component of MAB, but increasing evidence suggests that monotherapy with certain antiandrogens is an attractive alternative to castration-based therapy.The first antiandrogen in widespread use was the steroidal compound cyproterone acetate (CPA) followed by the nonsteroidal antiandrogens bicalutamide, flutamide and nilutamide 7,8,9. Eligibility Treatments Criteria and Allocated Patients with WHO performance status of 0-2 were eligible if they had measurable lymph node or soft tissue metastasis.Patients with detectable bone metastasis were also included (T1-4 N+MX or T1-4 NXM+). Since we aimed to include patients with a relatively favorable prognosis,patients with PSA values ≥100 ng/dl were not enrolled in the study. The other exclusion criteria were; histopathologic diagnosis other than adenocarcinoma, presence of cardiovascular and gastrointestinal problems which required medical therapy and liver enzyme elevations more over twice the normal levels. Furthermore, patients who had received previous hormonal therapy and radiotherapy to the metastatic sites were also excluded. 76 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group The study was conducted in accordance with respective European regulatory requirements, including the 1975 Declaration of Helsinki. Written consent was obtained from the ethics commitees of each participating center. A total of 120 patients were randomised to receive CPA ( 3x100mg/day orally) (Group 1, N: 60) versus medical or surgical castration (Group 2, N: 60). Patients randomised to the second treatment arm recommended surgical castration as the treatment procedure.In patients who refused surgical castration, medical castration by LHRH analogs was initiated. Any available LHRH agonists were acceptable in this respect. Quality control of the data and study performance were carried out in several steps. This included data verification and randomization by the data manager in the Data Center, review of patients’ documents for eligibility, compliance and endpoints by the Study Coordinator, and finally, computerized verification for errors and inconsistencies was carried out by the statistician. Size of Trial Population and Statistical Analysis Sample size: We initially estimated 381 patients to be recruited in the study with the power =0.80 and α=0.05. Median survival time to progression was considered 18 months for the CPA group and 23 months for the castration group. Baseline examinations included complete blood counts and biochemical tests (including PSA and testosterone measurements), computed tomography (CT) scan of the abdomen and pelvis and bone scintigraphy. Clinical examinations and biochemical tests were repeated every 3 months and bone scans were repeated every 12 months or as required.After disease progression or patient withdrawal from the therapy for any reason,patients were followed until death.On progression, treatment changes were left to the discretion of the investigator. Accrual time during which patients were recruited and additional follow-up time after the end of recruitment were considered as 36 months and 18 months respectively. The trial accrued less than one third of the number of patients required because of some inconveniences in recruitment, mostly due to the restrictions of the inclusion criteria. Endpoints and Evaluation of Efficacy The primary endpoints for this trial were overall and disease-spesific survival. Progression-free survival (PSA –progression) and testosterone decrease rate after the initiation of therapy were assessed as secondary endpoints. Progression was defined as the appearance of new metastatic sites (objective) or increase in PSA, increase in pain by two scores and worsening of the performance status by two scores (subjective). Since this interim analysis was focused mainly on PSA-recurrence, PSA monitoring received the major attention; and increase in PSA value by 20% or more on two consecutive determinations one month apart was considered as biochemical recurrence.Progression-free survival was computed from the date of randomization to the date of disease progression.All of the events and side effects were reported to the Data Center as encountered. Statistical Analysis: Progression-free survival probabilities were calculated by the Kaplan-Meier Method.A comparison of Kaplan-Meier survival probabilities was performed by using the Logrank test. Comparisons of frequency distribution were performed by means of the X2-test and of continuous random variables by means of the Wilcoxon rank sum (MannWhitney) test. A p-value of less then 0.05 was considered significant. All p-values were two-sided. RESULTS The baseline characteristics and prognostic factors of the 120 randomized patients at entry were well-balanced between the two arms with respect to age,PSA value,node and metastatic status etc.The only parameters for which a significant difference in baseline values were noted as Alkalen phosphatase, Hb 77 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group and Htc.The patients baseline characteristics are shown in Table I. difference with regard to PSA-progression in the two groups in the 24 month followup(p=0.616) (Fig.2). There were a total of 10 deaths (4 in the first, 6 in the second group) so far. Only 4 (2 in both groups) were attributed to prostate cancer. Obviously in this step of the trial, survival data is not available; thus, the primary endpoints have not yet been reached. Further follow-up is awaited. As the study did not reach its maturity with respect to time; more emphasis was put on the PSA decline and PSA-progression.Median PSA values revealed a favorable decline in both groups and there was no statistical difference between the PSA values at 3,6 and 12 months in the two arms (Table II). Another concern was whether median testosteron levels would reach the castration levels in both groups. Upon evaluation on the third month, the castrate levels of testosteron were achieved as 19.0 ng/dl (9% of initial value) and 17.0 ng/dl (6.7% of initial value) in Groups 1 and 2, respectively. This difference was also insignificant (p>0.05), (Fig.1). The overall safety profile of both treatments was acceptable. No severe cardiovascular and/or gastrointestinal side effects and/or increases in liver function tests or serum alkaline phosphatase changes have been encountered up to date (p>0.05) (Figs. 3a,b,c). However, erectile dysfunction was universal and almost every patient has suffered from loss of libido and/or erectile disfunction. The median follow-up period of the patients was 24 months ( 23 months in the CPA group and 24 months in the castration group). The number of events in the groups was 12 and 20 respectively (Table III). According to Log Rank test evaluations, there was no Table 1. Patients’ baseline characteristic Castration P Value 75 (65-97) 75 (51-86) 0.235 Lymph node positivity* 15/38 14 / 45 0.426 Bone metastases 47/58 46 / 57 0.397 42(2.10-98) ng/dl 42 (5.6-99) ng/dl 0.825 1.04(0.10-6.32) ng/dl 1.1 (0.64-4.0) ng/dl 0.715 CPA Age (median,range) PSA values (median, range) Kreatinin (median,range) Alkalen phosphatase (median,range) Hb (median,range) 143(12-1565) 205 (39-1235) 0.011 13.1(5.75-16.0) 13.7 (7.40-16.4) 0.009 Htc ( median,range) 39.0(16.2-55) 40.6 (21.9-48.3) 0.01 *Not every patient was evaluated with CT 78 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group Table II. Median PSA decline after the treatment 6 months N, ng/dL (% initial value) 3 months Baseline N, ng/dL N, ng/dL (% initial value) (% initial value) 12 months N, ng/dL (% initial value) CPA (Group1) n=58, 42.0 n=51, 3 (7) n=45, 1.35 (3.2) n=22, 0.875 (2) Castration (Group2) n=57, 42.0 n=49, 2.13 (5) n=46, 1.05 (2.5) n=33, 0.87 (2) p> 0.05 (in all comparisons) Fig. 1: Baseline and 3rd month testosterone median values in CPA (Group1) and Castration (Group 2) groups. Table III. PSA-progression Analysis for Time Total No. events No. censored % censored Group 1 (CPA) 60 12 48 80.00 Group2 (Castration) 60 20 40 66.67 Total 120 32 88 73.33 79 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group Figure 2: Progression-free Kaplan-Meier survival probabilities for CPA (group1) and Castration (group2) patients Figure 3a: SGPT median values in Group1(CPA) versus Group2 (Castration) Figure 3b: SGOT median values in Group1(CPA) versus Group2 (Castration) 80 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group Figure 3c: Alkalene Phosphatase median values Group1 (CPA) versus Group2 (Castration) Surgical or medical castration results in the disappearance or marginal decline of adrenal androgens that are likely to possess intrinsic androgenic activity16. Therefore, men who undergo castration still have relatively high levels (up to 40%) of DHT and 5-10% of T, presumably derived from adrenal precursors17. MAB as a concept of treatment for prostate cancer is the simultaneous complete elimination or blockade of testicular and adrenal androgens18. Since 1989, several randomized trials have suggested that MAB prolongs survival of the patients with advanced prostate cancer, compared to castration alone19,20. However, in 1998, Eisenberger et al.21 reported a randomized trial of 1.387 patients with metastatic prostate cancer who were all treated with surgical castration with placebo or flutamide21. There was no statistically significant survival advantage in favour of MAB. In 2000, the Prostate Cancer Trialists’ Collaborative Group performed a meta-analysis of 27 trials of MAB versus castration monotherapy involving 8.275 patients6. This study indicated a small difference in overall survival at 5 years in favor of MAB [25.4% vs 23.6%]. It is also reported that MAB is associated with more side effects,which have a negative impact on quality of life (QOL). Since MAB has lost its initial popularity as an antiandrogen deprivation approach, a growing DISCUSSION Since the first observation by Huggins and Hodges in 1941 2, hormonal therapy remained the main therapeutic option for advanced prostate cancer. So far, multiple strategies have been used to reduce the serum levels of androgens or to interfere with their function via the androgen receptor (AR). The classical form of androgen deprivation is surgical castration by bilateral orchiectomy.This is the most immediate method to reduce circulating testosterone(T) by > 90% within 24 hours without any risk of a paradoxical flare of the disease 10. Although surgical castration may be underused in our time,some studies suggest that many patients prefer this approach for reasons of convenience and cost11. Reversible medical castration dates back to the 1940’s. This was achieved by the administration of dietylstilbesteol (DES), a semi-synthetic estrogen compound12. Due to the high incidence of cardio-vascular (CV) toxicity and gynecomastia observed in patients receiving DES; this sort of androgene ablation has generally been abondoned today12,13. The development of LHRH analogues, obtaining medical castration with significantly fewer CV events and lack of gynecomastia,has led to a dramatic change in the treatment of advanced prostate cancer. The side effects of LHRH agonists include hot flashes, loss of libido and osteoporosis14,15. 81 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group interest has emerged in using antiandrogens as monotherapy in metastatic prostate cancer. The efficacy, tolerability and QOL benefits of bicalutamide (B) monotherapy vs castration were assessed in some phase III studies with locally advanced or metastatic prostate cancer22-25. Data emerging from these studies support the use of B monotherapy as an alternative to castration in patients with advanced disease, since the survival outcome is similar. However, this is true especially in well or moderately differentiated tumours;whereas, in patients with poor prognostic factors, antiandrogen monotherapy is inferior to castration in terms of overall survival and time to progression. CPA is a progestational antiandrogen and the first antiandrogen used for the treatment of advanced prostate cancer in Europe. It competes with androgens for the binding to the AR, as well as possessing antigonadotropic activity that results in a rapid and sustained 70-80% decrease in T levels8,26. There are limited and conflicting data on the use and effectiveness of steroidal antiandrogen CPA as a monotherapy in locally advanced and metastatic prostate cancer. In the first large phase III clinical study conducted by EORTC-GU Group27, 295 locally advanced prostate cancer patients were randomised into three treatment groups as: DES 3 mg/day, CPA (250mg/day) and Medroxyprogesterone acetate (MPA) ( 500 mg 3 times a week im.). With respect to the response of the primary tumour there was no statistical difference between CPA and DES. When the “time to progression” was compared, there was no significant difference between CPA and estrogens. Overall survival, including all causes of death in these two groups, was also similar. MPA was not effective in preventing progression and survival times were shorter with this agent. A comperative study of CPA and castration has reported survival data28. This was an open randomized study which compared goserelin, DES and CPA in two different cohorts of patients (arms A and B). CPA was associated with significantly poorer median survival (64 weeks) than goserelin (>194 weeks) in arm A, but no difference was seen in arm B (130 vs 132 weeks, respectively). A further study comparing CPA monotherapy, goserelin and MAB (goserelin plus CPA) found that CPA was less effective than goserelin, but with similar results to the MAB regimen in terms of delaying progression. However, survival data was not available29. Therefore, it is difficult to draw any definite conclusion about the relative efficacy of CPA and castration from these data. Our study offers encouraging results for CPA therapy in terms of PSA response; and disease-specific survival rates will be identified in the further steps of this trial. If PSA-progression is considered as a surrogate marker for survival;one can make a prediction that this would translate into a similar survival time in this study population as well. CPA has dual action as a peripheral testosterone receptor blocker and as a central agent on the hypothalamus to decrease overall serum testosterone to castrate levels26-29. Hence, it can be regarded as the only antihormone therapy that causes complete androgen blockade as monotherapy. The effectiveness of CPA in achieving castrate testosterone levels has been well-established in a recent study, which revealed that a nearcastrate serum testosterone was reached on day 7 30. Herein, we evaluated testosterone levels in all the patients every 3 months and although lower in the castration group, no statistically significant difference was encountered. This may also be encouraging for CPA having the same therapeutic efficacy as castration. In a recent study which compared flutamide versus CPA treatments in advanced prostate cancer patients; the two monotherapy arms showed similar efficacy in terms of survival and time to progression, but a clearly more pronounced toxicity in the FLU arm31. Moreower, FLU has not been found superior to CPA with regard to sexual functions. In our study, the side effects and QOL in the treatment arms have not been assessed. Indeed, most of the patients were impotent from the beginning. Therefore, sexual interest was not a major concern among the patients. Nevertheless, almost all 82 Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group 8. of the patients have been affected to a degree in terms of libido and erectile functions. On the other hand, no serious advers events and no withdrawals due to toxicity were reported, which indicates CPA therapy as a safe and tolerable option. 9. 10. This randomized, prospective study of CPA and castration in patients with metastatic prostate cancer has not so far revealed any significant difference in progression-free survival. The study is not mature, however, so the survival endpoints have not been met. The study is ongoing. Nevertheless, we think that the follow-up period has been sufficient for us to draw the following conclusion: the initial efficacy and tolerability benefit of monotherapy leads us to indicate that this therapy is safe and acceptable. So, less agressive endocrine management methods may also be considered in this subject. 11. 12. 13. 14. 15. 16. ACKNOWLEDGEMENTS The authors would like to thank to the entire urology team from 19 Urology Centers who gave an unrestricted support to this study. They also acknowledge the support of Shering AC Company for their willing effort in collecting data and all the secretarial work. 17. 18. 19. REFERENCES 1. 2. 3. 4. 5. 6. 7. Anderson J. Treatment of prostate cancer-The role of primary hormonal therapy. Eur Urol 2003; 132-139. Huggins C, Hodges CV. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293-297. The Veterans Administration Co-operative Urological Research Group (1967) Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011-1017. Vogelzang NJ, Chodak GW, Soloway MS, et al. Goserelin versus orchiectomy in the treatment of advanced prostate cancer:final results of a randomized trial; Zoladex Prostate Study Group. Urology 1995; 46:220-226. Kaisary AV, Tyrell CJ, Peeling WB, Griffiths K (1997) Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostate carcinoma. Br J Urol 1997; 32:391-396 Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet 2000;355:1991-1998. Anderson J. The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU, European Urology Update Series 2003; 9:455-461. 20. 21. 22. 23. 24. 83 Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: Current status and future prospects. The Prostate 2004; 61:332-353. Iversen P, Melezinek I, Schmidt A. Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function. BJU International 2001; 87:47-56. Maatman TJ, Gupta MK, Montie JE. Effectiveness of castration versus intravenous estrogen therapy in producing rapid endocrine control of metastatic cancer of the prostate. J Urol 1985;133:620-621. Chodwick DJ,Gillatt DA,Gingell JC.Medical or surgical orchiectomy:The patients’ choice.BMJ1991; 302:372. The Leuprolide Study Group Group. Leuprolide versus diethylstillbestrol for metastatic prostate cancer. N Eng J Med 1984; 311:1281-1286. Chang A, Yeap B, Davis T, et al. (1996) Doubleblind,randomized study of primary hormonal teratment of stage D2 prostate carcinoma: Flutamide versus diethylstilbestrol. J Clin Oncol 1996; 14:2250-2257. Labrie F, Belanger A, Susan L, et al. History of LHRH agonist and combination therapy in prostate cancer. Endoc Relat Cancer 1996; 3:243-278. Stege R. Potantial side effects of endocrine treatment of long duration in prostate cancer. Prostate 2000; (Suppl 10):38-42. Miyomoto H, Chang C. Antiandrogens fail to block andrositenedione-mediated mutated androgen receptor transactivation in human prostate cancer cells. Int J Urol 2000; 7:32-34. Galler J. Rationale for blockade of adrenal as well as testicular androgens in the treatment of advanced prostate cancer. Semin Oncol (Suppl 1) 1985;12::28-35. Schröder FH. Endocrine treatment of prostate cancerrecent developments and the future. Part 1: MAB, early vs delayed endocrine treatment and side-effects. BJU International 1999; 83:161-170. Crawford ED, Eisenberger MA, Spaulding JT, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Eng J Med 1989;321:419424. Denis LJ, Whelan P, deMoura JCL, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: A phase III EORTC trial (30853). Urology 1993;42:119132. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Eng L Med 1998; 339:1036-1042 . Tyrrell CJ, Kaisary AV, Iversen P et al. A randomized comparison of Casodex (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998; 33:447-456. Iversen P, Tyrrell CJ, Kaisary AV, et al. Casodex (bicalutamide) 150 mg-monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer:results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998; 51:389-396. Boccardo F, Barichello M, Battaglia M, et al. Italian Prostate Cancer Group.Bicalutamide monotherapy versus Flutamide plus Goserelin in Prostate Cancer: Updated results of a multicentric trial. Eur Urol 2002; 42:481-490. Marmara Medical Journal 2007;20(2);75-84 Yasar Beduk, et al. The comparison of the efficacy of cyproterone acetate and castration monotherapies in metastatic prostate cancer: a multicenter study of aTturkish uro-oncology group 25. Sciarra A, Cardi A, DiSilverio F. Antiandrogen monotherapy: recommendations for the treatment of prostate cancer. Urol Int 2004; 72:91-98. 26. Goldenberg SL, Bruchovsky N. Use of ciproterone acetate in prostate cancer. Urol Clin North Am 1991;18:111-112. 27. Pavone-Macaluso M, de Voogt HJ, Viggiano G., et al. Comparison of DES, CPA and medroxyprogestrone acetate in the treatment of advanced prostatic cancer:final analysis of a randomized phase III trial of the European Organization for research on treatment of cancer urological group. J Urol 1986;136:624-631. 28. Moffat LE. Comparison of Zoladex, DES and CPA treatment in advanced prostate cancer. Eur Urol 18(Suppl 3):26-27. 29. Thorpe SC, Azmatullah S, Fellows GJ, O’Boyle PJ. A prospective, randomized study to compare goserelin acetate versus cyproterone acetate versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996; 29:47-54. 30. Appu S, Lawrentschuk N, Grills RJ, Neerhut G. Effectiveness of CPA in achieving castration and preventing LHRH analogue induced testosterone surge in patients with prostate cancer. J Urol 2005;174:140142. 31. Schröder FH, Whelan P, de Reijke TM, et al. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the EORTC protocol 30892. Eur Urol 2004;45:457-464. 84 ORIGINAL RESEARCH THE EFFECT OF NITROUS OXIDE ON POSTOPERATIVE NAUSEA AND VOMITING Hatice Türe, Arzu Takıl, Zeynep Eti, F. Yılmaz Göğüş Marmara Üniversitesi, Tıp Fakültesi, Anesteziyoloji ve Reanimasyon A.D., İstanbul, Türkiye ABSTRACT Objective: Postoperative nausea and vomiting (PONV) is a common problem and its cause is multifactorial. The relationship between PONV and nitrous oxide is under debate. The aim of this study was to evaluate the relationship between nitrous oxide and PONV in patients undergoing laparoscopic cholecystectomy. Patients and Methods: Forty premedicated female patients, ASA I or II, age 18-60 years and weigthing between 50-80 kg, were scheduled to undergo elective laparoscopic cholecystectomy. They were randomly assigned to two groups. Anaesthesia was induced in all patients with thiopental sodium, remifentanil and atracurium. Anaesthesia was maintained with sevoflurane, nitrous oxide in oxygen in group I and sevoflurane, air in oxygen in group II. Perioperatively remifentanil was infused in all patients. The patient’s PONV and pain scores were assessed 24 hours postoperatively. Results: In group I, PONV scores were significantly higher at the 1st and 4 th h postoperatively, however, there was no significant difference in group II. There was no significant difference in PONV and pain scores and the percentage of patients needing antiemetics between groups. No correlation was found between PONV and postoperative pain. Conclusion: Our data demonstrate that nitrous oxide does not increase the incidence or severity of PONV in patients undergoing laparoscopic cholecystectomy. Keywords: Nitrous oxide, Postoperative, Nausea, Vomiting NİTRÖZ OKSİDİN POSTOPERATİF BULANTI VE KUSMA ÜZERİNE ETKİSİ ÖZET Amaç: Postoperatif bulantı ve kusma (POBK) birçok nedenden kaynaklanan ve sık karşılaşılan bir problemdir. POBK ve nitröz oksit arasındaki ilişi yeterince araştırılmıştır.Bu çalışmada laparoskopik kolesistektomi geçiren hastalarda, nitröz oksitin POBK`ya etkisinin araştırılması amaçlanmıştır. Yöntem: Premedikasyon yapılmış, ASA I-II, 18-60 yas arasında, 50-80 kg ağırlığında, elektif laparoskopik kolesistektomi operasyonu geçirecek 40 kadın hasta çalışmaya dahil edildi. Hastalar randomize olarak 2 gruba ayrıldı. Tüm hastalara tiyopental sodyum, remifentanil ve atrakuryum ile anestezi indüksiyonu uygulandı. Anestezi idamesinde, grup I`de sevofluran ve nitröz oksit-oksijen karışımı,grup II`de sevofluran ve hava-oksijen karışımı kullanıldı. Tüm hastalara peroperatif remifentanil infüzyonu verildi. Hastaların POBK ve ağrı skorları 24 saat süre ile takip edildi. Bulgular: POBK skorları, grup I`de 1. ve 4. saatlerde diğer saatlere göre yüksekti, ancak grup II`de saatler arasinda istatistiksel fark saptanmadı. Gruplar arasında, POBK ve ağrı skorları, antiemetik ilaç ihtiyacı olan hasta yüzdesi açısından fark saptanmadı. Hastaların POBK ve ağrı skorları arasında ilişki saptanmadı. Sonuç: Çalışmamız sonucunda, laparoskopik kolesistektomi operasyonu geçiren hastalarda, peroperatif kullanılan nitröz oksidin, postoperatif bulantı ve kusmanın sıklığı ve şiddetini arttırmadığı sonucuna varılmıştır. Anahtar Kelimeler: Nitröz oksit, Postoperatif, Bulantı, Kusma Corresponding author: Hatice Türe, M.D. Marmara Üniversitesi Tıp Fakültesi, Anesteziyoloji ve Reanimasyon A.D., Altunizade, İstanbul, Türkiye e-mail: htcture@yahoo.com 85 Marmara Medical Journal 2007;20(2);85-91 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting 3-5 mg/kg and remifentanil 1mgr/kg IV. Atracurium 0.5 mg/kg IV was administered to achieve muscle relaxation prior to tracheal intubation. After tracheal intubation a nasogastric tube was inserted and kept in place until just before extubation. Anaesthesia was maintained with 2% sevoflurane, 70% nitrous oxide in oxygen in group I and 2% sevoflurane, 70% air in oxygen in group II. Perioperatively, remifentanil was infused in all patients at a rate of 0.5 mgr/kg/min. The sevoflurane concentration was titrated to maintain mean arterial pressure and heart rate within 20% of baseline values. The lungs were ventilated mechanically to maintain the end tidal carbon dioxide pressure between 3540 mmHg. Heart rate, non-invasive arterial blood pressure, oxygen saturation and end tidal carbon dioxide pressure were measured and recorded every five minutes during surgery. In both groups, diclofenac sodium 75 mg IM was administered 30 minutes before the end of surgery. Following the last skin suture, 10 ml 0.25% bupivacaine was infiltrated at the incisions and the remifentanil infusion was discountinued. INTRODUCTION In the literature, postoperative nausea and vomiting (PONV) has been variously described as the “big little problem,” the “final therapeutic challenge” for the anaesthesiologist, and the “big, big problem” of the ambulatory surgery1,2. The cause of PONV is multifactorial. Some of the factors are well known, although others remain unknown or poorly understood. Studies have attempted to identify factors associated with PONV and to predict which patients are at the highest risk for this complication3,4. These factors may be related to the patient, the surgical procedure, or the choice of anaesthetic5. However, one of the factors contributing to PONV is the use of nitrous oxide during anaesthesia6. Several studies investigating the cause and effect relationship between PONV and nitrous oxide in adults have produced conflicting results, some claiming that nitrous oxide increases PONV7,8 while others were unable to confirm these findings6,9. In this prospective, randomized, double-blind study, the role of nitrous oxide anaesthesia in increasing PONV was studied in female patients undergoing laparoscopic cholecystectomy. The patients were then extubated and transported to the postanaesthetic care unit (PACU). Routine PACU management included recording of vital signs. Oxygen (6 lt/min) was administered on admission and discontinued before discharge to the ward. After the patient arrived in the PACU, a blind investigator observed the patient postoperatively. The patient’s PONV and pain scores were assessed at 30 minutes, 1st ,2nd ,4th , 6th ,12th , and 24th hour postoperatively. PONV scores ranged from 0 to 3 (0: no nausea and vomiting, 1: mild nausea not vomiting and not requiring treatment, 2: moderate nausea, mild vomiting and requiring treatment, 3: severe vomiting). Metoclopramide 20 mg IV was administered when the PONV score was greater than 1. The incidence of nausea and vomiting separately during the early (0-6 h) and delayed (6-24 h) period and the percentage of patients requiring antiemetic therapy were also recorded Pain intensity was assessed with the PATIENTS AND METHODS After the approval of the Institutional Ethics Committee and the patients’ written consent, 40 female patients, ASA physical status I or II, aged 18-60 years and weighing between 50-80 kg, scheduled for elective laparoscopic cholecystectomy were studied. They were randomly assigned to two study groups of 20 patients each. Patients with significant cardiac, respiratory, hepatic, renal or hematologic disorders, contraindications to administration of the study drugs, history of gastrointestinal bleeding, monoamino oxidase inhibitor therapy, alcohol abuse and motion sickness or previous PONV were excluded from the study. Forty-five minutes prior to the induction of anaesthesia, all the patients were premedicated with midazolam 0.07 mg/kg and atropin 0.015 mg/kg IM. Anaesthesia was induced in all patients with thiopental sodium 86 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting 5 point verbal pain scale (0; no pain, 1: mild pain, 2: moderate pain, 3: severe pain, 4: excruciating pain). Meperidine 1 mg/kg IV was administered when the pain score was greater than 1 (until a subsequent pain score was <2). and 10% in group II during the delayed period (6-24 h) (p>0.05). The incidence of vomiting during the early period was 40% in group I and 25% in group II while it was 5% in group I and group II during the delayed period (p>0.05). 40% of the patients in group I and 55% of group II did not experience PONV symptoms during 24 h postoperatively. In group I, the PONV scores were significantly increased at 1st and 4th h (p<0.05) but there was no significant change in group II (Figure I). However, no difference was found in the PONV scores of patients between groups. Eight patients (40 %) in group I and 5 patients (25 %) in group II required antiemetic therapy once or more time during the 24 h postoperatively (Table II). There was no significant difference in the percentage of patients requiring antiemetic therapy between groups (Table II). The χ2 test with Fisher correction was utilized to analyze differences between groups in demographics and the incidence of PONV. Pain and PONV scores were compared by using repeated measures of ANOVA and the student’s t-test. P<0.05 was considered as significant. All data were recorded as mean ± SD. RESULTS There was no significant difference between groups in the demographic characteristics of the patients and duration of the operation (Table I). Intraoperatively, the mean amount of remifentanil was similar in the two groups. Twenty patients (100 %) in group I and 18 patients (95 %) in group II required additional analgesics postoperatively (Table II). There was no significant difference in postoperative pain scores between groups (Figure 2). No significant correlation was found between PONV and pain. There was no significant difference in the incidence of nausea or vomiting between the groups during the 24 h postoperative period (Table II). The incidence of nausea during the early period (0-6 h) was 20% in group I and 15% in group II while it was 20% in group I Table I. Demographic characteristics, duration of surgery and total remifentanil dose (mean± SD). N2O+O2 (n=20) 39.85± 11.11 59.9± 8.08 60± 9.2 1840± 495.8 14/6 Age (yr) Weight (kg) Duration of surgery (min) Dose of remifentanil (µgr) ASA class (I/II) 87 Air+O2 (n=20) 48.35± 11.61 64.8± 10.35 58± 7.05 1891± 510.2 11/9 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting Table II. Incidence and Severity of Postoperative Nausea, Vomiting and Pain (%). N2O+ O2 (n:20) Air+O2 (n:20) PONV (n) None Only nausea Vomiting 8 (40 %) 12 (60 %) 8 (40 %) 11(55 %) 9 (45 %) 5 (25 %) Antiemetic medication needed (n) None Once More often 12 (60 %) 4 (20 %) 4 (20 %) 15 (75 %) 1 (5 %) 4 (20 %) Pain (n) None Mild Moderate Severe Persistent 0 0 18 (95 %) 8 (40 %) 2 (10 %) 2 (10 %) 0 17 (85 %) 2 (10 %) 1 (5%) Figure 1. PONV scores of patients within 24 hours (mean ± SD). 88 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting Figure 2. Pain scores of patients within 24 hours (mean ± SD). during general anaesthesia. Divatia et al15 performed a meta analyses of published randomized controlled trials studying the effect of nitrous oxide on PONV. Twentyfour studies were found to be eligible for meta analyses. There were only 5 statistically significant “positive” trials showing that omission of nitrous oxide decreased PONV. There were 15 “negative” trials and no effect in 4 trials. However they concluded that omission of nitrous oxide can reduce the risk for PONV by nearly 30%, stressing the need for further studies and randomized controlled trials. The main reason for the conflicting results is the methodological problems in the studies looking at PONV. Kortilla4 and Watcha5 stated that it is important to have an appropriate study design whereby all confounding factors are evenly distributed between the study groups and this is achieved by limiting the study to a standardized surgical procedure during a standardized anaesthetic and assigning patients to receive an intervention according to a predetermined randomized double blind method. Also populations studied in the PONV trials should represent a reasonable clinically relevant baseline risk16. In our study; we studied a population having relevant risk factors: those who were female, non-smoker,undergoing laparoscopic surgery, and those who were DISCUSSION Postoperative nausea and vomiting have been associated for many years with the use of general anaesthetics for surgical procedures 5,10 The incidence of PONV is approximately 9% to 10% during the stay in the post anaesthesia care unit and increases to 30% during the first 24 hours postoperatively, leading to delayed discharge or, rarely, serious complications11. There are hundreds of published randomized controlled trials investigating the efficacy of interventions which are thought to have impact on the incidence of PONV. However there are still many unanswered questions12. There have been attempts to identify patient related and non-related risk factors for PONV. Sinclair et al13 in their prospective study with 17638 outpatients concluded that age,sex,smoking status, previous history of PONV,type and duration of anaesthesia and type of surgery are independent predictors of PONV. Also Apfel et al14 found that the four main risk factors for PONV were female gender, prior history of PONV and motion sickness, nonsmoking and the use of opioids. Among all these risk factors, there have been several studies evaluating the effect of anaesthetics, in particular nitrous oxide. However the results are conflicting and today there is still no consensus for omitting nitrous oxide 89 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting administered opioids peri and postoperatively. We also standardized the surgical procedure and anaesthetics as all patients received the same anaesthetics (thiopental, remifentanil and sevoflurane) with nitrous oxide being the only variable. Postoperative pain is another predicting factor for PONV18,19. Pain significantly prolongs recovery and discharge times and contributes to postoperative nausea and vomiting, often leading to unanticipated admission after ambulatory surgery. Cholecystectomy can cause inflammation or local irritation around the gall bladder bed,liver, diaphragm and/or peritoneum, exacerbating pain20. The intensity of pain is most severe during the first 2-3 h after the laparoscopic cholecystectomy21. Postoperative pain control for laparoscopic cholecystectomy is attainable using a multimodal pain management strategy. Michaloliakua20 stated that the concomitant use of local anaesthetics, nonsteroidal antiinflammatory drugs and opioids proved to be highly effective after laparoscopic cholecystectomy. Although our strategy for postoperative pain control included intramuscular diclofenac Na and incisional bupivacaine infiltration, the percentage of patients needing additional opioid analgesics was very high in the two groups (100% in group I and 95% in group II). However, no correlation was found between PONV and pain. Watcha5 and Tramer12 in their reviews of PONV suggested that nausea and vomiting must be considered separate endpoints for more precise results. Also Kortilla4 stated that the outcome should be included in studies on PONV as the need to give antiemetic and the number of patients needing antiemetics are good endpoints for statistical analyses. In our study; we considered nausea and vomiting and the number of patients needing antiemetics as separate endpoints and found no significant difference in the incidence of nausea or vomiting and the percentage of patients needing antiemetics when nitrous oxide was omitted. According to Watcha5, separate time-based analyses should be performed for the early (0-6 h) or delayed (624 h) postoperative period in the studies. Short term efficacy has an economic impact, mainly in day surgery where patients are meant to be discharged within hours after surgery; while long term efficacy is a better indicator of antiemetic efficacy and patient comfort16. We also studied the early and delayed effects of nitrous oxide on PONV and could not find a significant difference. It is commonly observed that the use of opioids during surgery increases the incidence of PONV3,12,14. In our study, remifentanil was infused perioperatively. This agent has a pharmocokinetic profile characterized by rapid equilibration with the central compartment, easy titrability and a short termination half-life independent of infusion duration. Our results about the postoperative additional analgesics also imply the need for a longer-acting opioid for postoperative analgesia22. Whether there is a synergistic effect between opioids and nitrous oxide in increasing emetic symptoms in the postoperative period is still a conjecture7. Our results do not support this idea since we used intraoperative and postoperative opioids (remifentanil and meperidine in all patients but did not find a higher incidence of nausea or vomiting in the nitrous oxide group as in the study by Pandit et al6. In the reviews about PONV, it was emphasized that the effect of omitting nitrous oxide was most pronounced for postoperative emesis in adults undergoing procedures known to be associated with a high risk for PONV and have little influence on nausea itself5,12,15. In our study, although the patients were female,nonsmoker,administered opiods and underwent laparoscopic surgery,the omission of nitrous oxide did not have a significant influence on either nausea or vomiting. The decrease in PONV when nitrous oxide is avoided may reflect the use of higher inspired oxygen concentration rather than a direct effect of nitrous oxide17. We used air instead of nitrous oxide with the same inspired oxygen concentrations in all patients. We concluded that nitrous oxide did not increase the incidence of nausea and 90 Marmara Medical Journal 2007;20(2);85-91 Hatice Türe, et al The effect of nitrous oxide on postoperative nausea and vomiting 12. Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part I. Efficacy and harm of antiemetic interventions, and methodological issues. Acta Anaesthesiol Scand 2001; 45: 4-13. 13. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted? Anesthesiology 1999; 91: 109-118. 14. Apfel CC, Laara E, Koivuranta M,Greim CA, Roewer N. A simplified risk sore for predicting postoperative nausea and vomiting. Anesthesiology 1999; 91: 693-700. 15. Divatia JV, Vaidya JS, Badwe RA,Hawaldar RW. Omission of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting. A metaanalysis. Anesthesiology 1996; 85: 1055-1062. 16. Tramer MR. A rational approach to the control of postoperative nausea and vomiting: evidence from systematic reviews. Part II. Recommendations for prevention and treatment,and research agenda. Acta Anaesthesiol Scand 2001; 45: 14-19. 17. Greif R, Laciny S, Rapf B, et al. Supplemental oxygen reduces the incidence of postoperative nausea and vomiting. Anesthesiology 1999; 91: 1246-1252. 18. White PF, Shafer A. Nausea and vomiting: Causes and prophylaxis. Semin Anesth 1988; 6: 300-308. 19. Anderson R, Krohg K. Pain as a major cause of postoperative nausea. Can Anaesth Soc J 1976; 23: 366369. 20. Michaloliakua C, Chung F, Sharma. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996; 82: 44-51. 21. Narchi P, Lecoq G, Fernandez H, Benhamou D. Intraperitoneal local anesthetics and scapular pain following daycase laparoscopy. Lancet 1991; 338:15691570. 22. Beers RA, Calimlim JR, Uddoh E, Esposito BF, Camporesi EM. A comparison of the cost-effectiveness of remifentanil versus fentanil as an adjuvant to general anesthesia for outpatient gynecologic surgery. Anesth Analg 2000; 91: 1420-5. vomiting. In addition, nitrous oxide did not increase the percentage of patients needing antiemetic therapy in female patients undergoing laparoscopic cholecystectomy. REFERENCES 1. Fisher DM. The “big little problem” of postoperative nausea and vomiting; do we know the answer yet (editorial)? Anesthesiology 1997; 87: 1271-1275. 2. Kapur PA. The big “little problem”. Anesth Analg 1991; 73: 243-245. 3. Alexander GD, Skupski JN, Brown EM. The role of nitrous oxide in postoperative nausea and vomiting. Anest Analg 1984; 63: 17S. 4. Korttila K. The study of postoperative nausea and vomiting. Br J Anaesth 1992; 69 (suppl): 20S-23S. 5. Watcha MF. Postoperative nausea and emesis. Anesthesiology Clinics of North America 2002; 20: 471484. 6. Pandit UA, Malviya S, Lewis IH. Vomiting after outpatient tonsillectomy and adenoidectomy in children: the role of nitrous oxide. Anesth Analg 1995; 80: 230233. 7. Hopkins PM. Nitrous oxide: a unique drug of continuing importance for anaesthesia. Best Pract Res Clin Anaesthesiol 2005; 19: 381-389. 8. Lonie DS, Harper NJN.Nitrous oxide and vomiting. The effect of nitrous oxide on the incidence of vomiting following gynecological laparoscopy. Anaesthesia 1986; 141: 703-707. 9. Felts JA, Poler M, Spitznagel EL. Nitrous oxide, nausea and vomiting after outpatient gynecologic surgery. J Clin Anesth 1990; 2: 168-171. 10. Andrews PLR. Physiology of nausea and vomiting. Br J Anaesth 1992; 69 (suppl 1): 2S-19S. 11. Junger A, Hartmann B, Benson M, et al. The use of an anaesthesia information management system for prediction of antiemetic rescue treatment at the postanesthesia care unit. Anesth Analg 2001; 92: 12031209. 91 ORIGINAL RESEARCH THE EFFECTS OF SPERM MORPHOLOGY AND MOTILITY ON THE OUTCOME OF INTRACYTOPLASMIC SPERM INJECTION Vildan Karpuz1Aslı Gokturk2, Meral Koyuturk3 Department of Pathology,School of Medicine, Istanbul Science University , Istanbul, Turkey 2Istanbul Women’s Health and Fertility Center, Gumussuyu-Beyoglu, Istanbul, Turkey 3Department of Histology and Embryology, School of Medicine, Istanbul Science University , Istanbul, Turkey 1 ABSTRACT Objective: The outcome of intracytoplasmic sperm injection (ICSI) treatments was evaluated and compared with sperm morphology and motility classifications in order to determine whether strict criteria or motility could aid in predicting the ICSI outcome. Patients and Methods: Two-hundred and forty-two of the infertile couples admitted to the clinic, were selected and ICSI treatment was performed. In the study group, female partners were required to have at least 5 oocytes at metaphase II. For male partners only the presence of spermatozoa cells in the semen fluid was necessary. Semen analysis and motility was performed according to the World Health Organisation (WHO) criteria and sperm morphology was assessed according to Kruger’s criteria. Results: There was no significant difference for the ICSI outcome assessment parameters indicating that fertilization and pregnancy rates between the groups were based on the percentages of sperms morphology and motility. Conclusion: Sperm morphology and motility were accepted as best parameters to evaluate the outcomes of in vitro fertilization (IVF). However, our results showed that ICSI outcomes were independent from these valuable parameters for IVF. Keywords: Sperm morphology, Sperm motility, ICSI SPERM MORFOLOJİSİ VE MOTİLİTESİNİN İNTRASİTOPLAZMİK SPERM ENJEKSİYON SONUÇLARI ÜZERİNE ETKİLERİ ÖZET Amaç: İntrasitoplazmik sperm enjeksiyonu (ICSI) tedavi sonuçları, sperm morfoloji ve motilite sınıflandırmaları ile karşılaştırılarak değerlendirildi; bu çerçevede Kruger kesin kriterlerinin veya motilitenin, bu sonuçları tahminde yardımcı olup olamıyacağı araştırıldı. Yöntem: Kliniğe başvuran infertil çiftlerden, 242 si seçilerek ICSI tedavisi uygulandı. Çalışma grubundaki kadın partnerlerde Metafiz II oosit sayısı en az 5 ve üzerinde, erkek partnerlerde ise yanlızca semen sıvısında sperm bulunması gereği öngörüldü. Semen analizi ve motilite değerlendirmesi Dünya Sağlık Örgütü (WHO) kriterlerine göre gerçekleştirildi; sperm morfolojisi ise “Kruger’in kesin kriterleri”ne göre değerlendirildi. Bulgular: Sperm morfoloji ve motilite yüzdelerine göre oluşturulan gruplar içerisinde ICSI sonuçlarını değerlendirme parametrelerinden, fertilizasyon ve gebelik oranları arasında anlamlı bir fark saptanmadı. Sonuç: Sperm motilite ve morfolojisi in vitro fertilizasyon (IVF) sonuçlarının değerlendirilmesinde en iyi parametreler olarak kabul edilmektedir. Oysa ki bizim bulgularımız ICSI sonuçlarının IVF için değerli olan bu parametrelerden bağımsız olduğunu göstermektedir. Anahtar Kelimeler: Sperm morfolojisi, Sperm motilitesi, ICSI Corresponding author: Vildan Karpuz,M.D. Chairman, Department of Pathology, School of Medicine, Istanbul Science University,Istanbul, Turkey e-mail: vildankarpuz@hotmail.com 92 Marmara Medical Journal 2007;20(2);92-97 Marmara Medical Journal 2007;20(2);92-97 Vildan Karpuz, et al. The effects of sperm morphology and motility on the outcome of intracytoplasmic sperm injection Initially, a spermiogram test was performed for the male partner. A general evaluation of the samples was performed according to WHO10 criteria and their morphological evaluation was done by Kruger strict criteria 11 . On the day of ICSI, an appropriate washing method was determined by reevaluation with respect to the number, motility and morphology. Ovarian stimulation was applied to the female partner to obtain more than one oocyte. During stimulation, urine or recombinant gonadotropins were combined with the gonadotropin releasing hormone (GnRH) agonist/antagonist. Mature oocytes were collected approximately 36-40 hours following urinary human chorionic gonadotropin (hCG) injection. ICSI procedure was performed after preparation of the oocytes. Fertilization was confirmed after 1618 h by the observation of two distinc pronuclei (2PN) and two polar bodies. The fertilization rate was calculated as the number of fertilized oocytes divided by the total number of mature oocytes for each couple. Embryo transfers were performed by the same clinician on day 2 or 3 according to the number and quality of embryos. Blood hCG levels were examined 14 days after the procedure (Β hCG Test. Diagnostics Corp.). Positive test value for pregnancy was > 5. Repeat test was required for patients with a result > 20. Those with a twofold or more increase were considered pregnant. We were not able to follow up pregnancies until labour since most of our patients lived in other cities and were lost to follow up. INTRODUCTION Since about half of the infertility cases are due to male factors, a detailed sperm analysis became the most important examination to be performed in the approach to the infertile couples. Basically, sperm count, motility and percentage of normal sperms are conventional criteria for semen quality 1. Among these parameters, sperm morphology and motility are the best criteria for demonstrating the fertilization capacity of a male 2-4. Sperm motility gives a measure of the integrity of the sperm axoneme and tail structures as well as the metabolic machinery of the mitochondria, and sperm morphology is a surrogate measure of the integrity of DNA packaging and the quality of spermatogenesis 5. When the effects of sperm morphology were examined from different aspects the following conclusions were drawn: sperm morphology was considered to be the best predictive factor in 6, natural fertilization intrauterine 7 insemination and ordinary in vitro fertilization 8,9. The aim of this study was to demonstrate the effects of sperm motility and sperm morphology on fertilization and pregnancy, in couples candidates for ICSI evaluated by means of a detailed sperm examination of the male partner. PATIENTS AND METHODS Two-hundred and forty-two patients admitted to our infertility center who had previously undergone ICSI and still wanted to have a child were included in the study. The study group consisted of male patients with sperm in normal semen fluid (sperm parameters were not taken into account) but free of total immotility or any major anomaly (globozoospermia, megalozoospermia) and female patients with metaphase two (MII) oocyte count ≥ 5. Following the assignment of our cases into two groups based on the percentages of sperm with normal morphology (≥5%, < 5%), a third group was formed from patients with a sperm count of <1 million/ml and not subjected to morphological examination. Examination Methods: Semen Analysis Sperm specimens were obtained by masturbation following sexual abstinence for three to five days. The sperm specimens were liquidified in a laminar flow chamber at 37 ºC. After liquidification, 10 µl of semen specimen was placed in a Makler chamber for the determination of spermatozoa count and motility. Also, for morphological evaluation, a smear was prepared by applying 10-20 µl of sperm specimen on a slide. 93 Marmara Medical Journal 2007;20(2);92-97 Vildan Karpuz, et al. The effects of sperm morphology and motility on the outcome of intracytoplasmic sperm injection the Diff Quick method. For this procedure, a Diff-Quick staining set (Allegiance Healthcare Corp., USA) was used. Two hundred sperm were counted for assessment, and examined under immersion oil with a (100X) phase contrast microscope. They were evaluated using Kruger strict criteria 11. Preparation of Semen Specimen: The sperm specimens were prepared by “concentration”, “gradient” or “swim-up” methods according to sperm count and motility. Sperm specimens with sperm counts less than 0.5 million/ml and motility less than % 10 were prepared by the concentration method. In this procedure, equal amounts of semen specimen and washing medium (G Sperm, Vitrolife) were mixed and transferred to a 15 ml conic tube and centrifuged at 2000 rpm for 10 minutes. The supernatant was removed and the pellet was mixed with 1 ml medium and centrifuged again. Thereafter supernatant was discarded, 0.3 ml culture medium (G Fert, Vitrolife) was added and incubated. The gradient method was used for specimens with sperm counts of less than 5 million/ml and poor motility or having too many scrap cells. For this procedure, 90% and 45% gradient media were prepared (Sperm Grad, Vitrolife). The following were placed in a conic tube in ascending order: 90% sperm grade medium, 45% sperm grade medium and 1 ml semen. The specimen was centrifuged at 1500 rpm for 20 minutes. The pellet on the base was taken by a pipette crossing the gradient and sperm layers, and transferred to a clean tube. It was mixed with 4 ml washing medium and centrifuged at 1500 rpm for 5 minutes. The supernatant was removed again and the pellet was diluted with 0.5-1 ml culture medium depending on the sperm count. Specimens with a good sperm count and motility were prepared with the swim up method. Equal amounts of specimen and washing medium (G Sperm, Vitrolife, Sweden) were placed in a conic tube and centrifuged at 1600 rpm for 10 minutes. After removing the supernatant, 0.5 ml culture medium (G Fert, Vitrolife, Sweden) conditioned with gas in a 5% CO2 incubator was added and placed in the incubator. All specimens were assessed for concentration and motility prior to storage in the incubator until the procedures. Assessment of Sperm Morphology Two slides were prepared from each patient for morphological assessment. A specimen of 10µl was placed on a slide and smeared with another slide and the preparation was left to dry. The dried specimens were stained with Assessment of Sperm Motility The motility of the semen specimen was assessed by using liquidified fresh semen.A Makler (Sefi Medikal Instr., Israel) counting chamber was used for counting. Motility assessment was performed by counting at least 200 sperm from 5 different areas according to WHO criteria 10.The sperms were scored for motility evaluation, expressed as grades a to d and the progressive motility rate was calculated as a percentage of (a+b). Statistical Analysis Two hundred and forty-two couples were divided into three groups on the basis of sperm percentages with normal morphology: group 1, ≥5% (n=100); group 2, >5% (n=90), and group 3 patients with sperm counts of less than 1 million/ml (n=52). Morphological evaluation was not performed for group 3. In the study groups, mean age, mean number of oocytes, mean MII oocyte number, fertilized oocyte percentage and mean embryo numbers transferred were calculated using the “Univariate Variance Analysis”. All couples were also divided, based only on motility rates ≥50% (n=119) and < 50% (n=123), without considering the morphological evaluation. In two groups, according to motility, the mean age, mean number of oocytes, mean MII oocyte number, fertilized oocyte numbers and mean embryo numbers transferred were calculated using the Student’s t-test. Pregnancy rates of all the groups according to morphology and motility were calculated by “Chi-Square Test”. Statistical significance was assessed at p <0.05. RESULTS In our study, the fertilization and pregnancy outcomes of ICSI treatment were assessed in 242 couples. Sperm morphology and motility values were classified to determine whether 94 Marmara Medical Journal 2007;20(2);92-97 Vildan Karpuz, et al. The effects of sperm morphology and motility on the outcome of intracytoplasmic sperm injection these parameters were helpful in estimating ICSI outcomes. 73.09%) and pregnancy rates (59, 54.4, and 57.7) in the groups. The fertilization rate was slightly decreased in the third group; however this did not reach statistical significance (Table I). There were no difference in the mean age of the female partners, the number of total oocytes, injected metaphase II oocytes and number of transferred embryos in all groups as presented in Table I-II. When we group the 242 couples of our study based only on motility rates, without considering the morphological evaluation, the mean of fertilized oocytes was 76.66% and 74.78% and the pregnancy rates were 58.80 and 55.30, respectively (Table II). There was no statistically significant difference between the two groups based on motility in terms of fertilization and pregnancy rates. The first group included couples with normal sperm morphology ≥5%, the second group included couples with normal sperm morphology < 5% and the third group was formed from patients with a sperm count of <1 million/ml and not subjected to morphological examination. There was no difference for ICSI outcome assessment parameters for fertilization (78.36, 74.26 and Table I: Groups based on sperm percentages with normal morphology ≥5% and >5%, and patients with sperm counts less than 1 million/ml for which morphological evaluation was not performed. P Sperm Sperm Sperm Morphology≥5 Morphology <5 Concentration<1mil/mil (n=100) (n=90) (n=52) Age 31.13±4.62 30.06±4.94 29.25±4.69 0.057 Total oocyte * 13.60±8.03 (12) 13.96±7.64 (13) 12.98±6.32 (12) 0.860 Metaphase II oocyte* 11.12±6.03 (10) 11.59±6.14 (10) 10.56±4.96 (9) 0.738 3.67±0.77 (4) 3.53±0.92 (3) 3.48±0.89 (4) Fertilization (%) 78.36±17.97 74.26±19.56 73.09 ±20.22 0.182 Pregnancy 59.0 54.4 57.7 0.813 Number of embryos transferred* (%) 0.417 * Mean±SD (Median value) Table II: Patients also divided into two groups according to progressive motility ≥ 50% or <50%. Motility ≥%50 Motility <50 (n=119) (n=123) Age 30.59±0.42 30.06±0.44 0.390 Total oocyte* 14.19±8.14 (13) 13.02±6.86 (12) 0.299 Metaphase II oocyte* 11.51±6.02 (10) 10.84±5.68 (10) 0.287 3.63±0.76 (4) 3.52±0.94 (4) 0.767 Number of embryos transferred* P Fertilization (%) 76.66±1.68 74.78±1.79 0.444 Pregnancy 58.80 55.30 0.578 (%) * Mean±SD (Median value) 95 Marmara Medical Journal 2007;20(2);92-97 Vildan Karpuz, et al. The effects of sperm morphology and motility on the outcome of intracytoplasmic sperm injection in higher amount in the sperm nuclei of infertile males 17,18. Also, the potential of having a normal pregnancy from embryos developed from sperms with abnormal head shapes was found to be lower 19. An inverse proportion was found between the increase of abnormal sperm count and chance of live birth and a longer the time to the first pregnancy was also reported 20. DISCUSSION For the semen analysis, traditional manual methods of concentration, motility and morphology measurements are currently the most important parameters for the examination of male infertility 11,12. The combination of sperm morphology, progressive motility percent and total motile sperm count has been demonstrated to be the best parameter to evaluate the fertility capacity of sperm in IVF 2-4. Parallel studies were examined and found out that the number of studies and cases that examined ICSI outcomes were less in literature when compared with the number of studies and cases that examined IVF outcomes. According to previous reports and our results in ICSI, fertilization may be achieved, even in the presence of a few motile sperm, because natural selection steps are skipped in the presence of abnormal sperm 21,22. According to results of published reports, four explanations were proposed to clarify for independency of ICSI outcomes from sperm morphology and motility. The first explanation is that normal sperm morphology is required to pass the zona pellucida and barriers in the female reproductive tract. All these barriers are crossed mechanically in the ICSI method 16,23. The second explanation is reports that sperms with abnormal shaped heads and immotile sperms reduce fertilization, implantation and pregnancy rates 19,23 . However, these sperms are usually not chosen by embryologists in the ICSI procedure 16. The third explanation is that the sperms chosen from the semen for the procedure may not reflect a clear morphology especially in low magnification. The fourth explanation is that the variations of minor defective sperms at organelle level may affect the ICSI outcomes 7. These ultrastructural changes can neither be detected by morphologists nor by embryologists in microscopic examinations. To test this last hypothesis, Bartoov et al. developed a method providing a detailed examination of a motile sperm in real-time and named it motile sperm organelle morphology examination (MSOME). The normal morphological structure of the sperm nucleus defined by MSOME has been positively correlated both with fertilization and pregnancy outcomes 24. The group demonstrated that sperm nucleus morphology is favorable for determining implantation and pregnancy outcomes compared to standard sperm morphology 25. Peter Svalander et al. have classified the semen specimens into three categories according to strict criteria in their study: excellent prognosis (>14%), good prognosis (4-14%) and poor prognosis 13. It was reported that total immotile sperm injection may have a negative effect on fertilization and pregnancy rates. Total absence of fertilization was demonstrated in outcomes of cases with total immotile sperms or round head sperms 14. On the other hand, Nagy et al. reported that samples prepared from fresh ejaculate sperm concentration and morphology had no effect on the ICSI outcomes in their study conducted in patients with entirely immotile spermatozoa 15. We have also found a correlation in fertilization and pregnancy rates with neither morphology nor motility. Our results confirm the findings; however, we have no results for immotile sperm injection outcomes. Nikolettos et al. have concluded that the chance of a successful pregnancy is low with severe anomalies of the sperm head shape even if fertilization has been achieved in these patients. Moreover, they reported that sperm decondensation defects and DNA anomalies might be the main factors affecting the fertilization capacity of sperm irrespective of its morphology 16. Evenson and Bianchi mentioned that loose packaged chromatin and damaged DNA were 96 Marmara Medical Journal 2007;20(2);92-97 Vildan Karpuz, et al. The effects of sperm morphology and motility on the outcome of intracytoplasmic sperm injection 8. Studies examining the relationship between ICSI outcomes, sperm morphology and aneuploidy have led us to question the ICSI methods in recent years. Palermo et al. have found an increasing aneuploidy rate in infertile patients undergoing ICSI when they examined the ICSI outcomes and aneuploidy rate in unselected infertile patients. The association between absence of pregnancy and increased aneuploidy was shown in the same study 26. 9. 10. 11. 12. In the light of these and our studies, we can say that sperm morphology and motility have no effect on the fertilization and pregnancy rates established in the ICSI procedure. However, it is suggested that these two parameters may have a possible effect on the continuing pregnancy and live birth rates. Although selection of spermatozoa with microscopically normal appearance by an embryologist is effective for increasing pregnancy rates, the effect of indiscernible nucleus anomalies on live birth rates will be clarified by future studies. 13. 14. 15. 16. 17. Acknowledgement: This study was approved by T.C. Kadir Has University Ethical Commity with the serial number 2004/002 on March 24, 2004. 18. 19. REFERENCES 1. 2. 3. 4. 5. 6. 7. Check JH, Bollendorf A, Pres M, Blue T. Standard sperm morphology as a predictor of male fertility potential. Arch Androl 1992; 28: 39-41. Lundin K, Soderlund B, Hamberger L. The relationship between sperm morphology and rates of fertilization, pregnancy and spontaneous abortion in an in-vitro fertilization/intracytoplasmic sperm injection programme. Hum Reprod 1997; 12: 2676-81. Bonde JP, Ernst E, Jensen TK, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 10: 1172-76. Enginsu ME, Pieters MHEC, Dumoulin JCM, Evers JLH, Geraedts JPM. Male factor as determinant of in vitro fertilization outcome. Hum Reprod 1992; 7: 113640. Pacey AA. Is quality assurance in semen analysis still really necessary? A view from the andrology laboratory. Hum Reprod 2006; 21:1105-9. Bartoov B, Eltes F, Pansky M, et al. Improved diagnosis of male fertility potential via a combination of quantitative ultramorphology and routine semen analyses. Hum Reprod 1994; 9: 2069-74. Berkovitz A, Eltes F, Soffer Y, et al. ART succes and in vivo sperm cell selection depend on the ultramorphological status of spermatozoa. Andrologia 1999; 31: 1-8. 20. 21. 22. 23. 24. 25. 26. 97 Mashiach R, Fisch B, Eltes F, et al. The relationship between sperm ultrastructural features and fertilizing capacity in vitro. Fertil Steril 1992; 57: 1052-57. Kruger TF, Swanson RJ, Acosta AA, et al. Predictive value of abnormal sperm morphology in in vitro fertilization. Fertil Steril 1988; 49: 112-17. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction, 4th edition. Cambrige University Press, Cambridge, 1999; 1-125. Kruger TF, Menkveld R, Stander FrSH, et al. Sperm morphologic features a prognostic factor in in vitro fertilization. Fertil Steril 1986; 46: 1118-23. Martinez C, Marc C, Azcarate M, Pascual P, Aritzeda JMA. Sperm motility index: a quick screening parameter from sperm quality analyser-IIB to rule out oligo- and astenozoospermia in male fertility study. Hum Reprod 2000; 15: 1727-33. Svalander P, Jakobsson AH, Forsberg AS, Bengtsson AC, Wikland M. The outcome of intracytoplasmic sperm injection is unrelated to ‘strict criteria’ sperm morphology. Hum Reprod 1996; 11: 1019-22. Lui J, Nagy Z, Tournaye H, et al. Analysis of 76 total fertilization failure cycles out of 2732 intracytoplasmic sperm injection cycles. Hum Reprod 1995; 10: 2630-36. Vandervorst M, Tournaye H, Camus M, et al. Patients with absolutely immotile spermatozoa and intracytoplasmic sperm injection. Hum Reprod 1997; 12: 2429-33. Nikolettos N, Kupker W, Demirel C, et al. Fertilization potential of spermatozoa with abnormal morphology. Hum Reprod 1999; 14: 47-70. Evenson DP, Darzynkiewicz Z, Melamed MR. Relation of mammalian sperm chromatin heterogeneity to fertility. Science 1980; 210:1131-33. Sakkas D, Urner F, Bianchi PG, et al. Sperm chromatin anomalies can influence decondensation after intracytoplasmic sperm injection. Hum Reprod 1996; 11: 837-43. Tasdemir I, Tasdemir M, Tavukcuoglu S, Kahraman S, Biberoglu K. Effect of abnormal sperm head morphology on the outcome of intracytoplasmic sperm injection in humans. Hum Reprod 1997; 12: 1214-17. Bostofte E, Serup J, Rebbe H. Relation between morphologically abnormal spermatozoa and pregnancies obtained during a twenty-year follow-up period. Int J Androl 1982; 5: 379-86. Van Steirteghem AC, Nagy Z, Joris H, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod 1993; 8:1061-66. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340:17-8. Kahraman S, Akarsu C, Cengiz G, et al. Fertility of ejaculated and testicular megalohead spermatozoa with intracytoplasmic sperm injection. Hum Reprod 1999; 14: 726-30. Bartoov B, Berkovitz A, Eltes F, et al. Real-time fine morphology of motile human sperm cells is associated with IVF-ICSI outcome. J Androl 2002; 23: 1-8. Berkovitz A, Eltes F, Yari S, et al. The morphological normalcy of the sperm nucleus and pregnancy rate of intracytoplasmic injection with morphologically selected sperm. Hum Reprod 2005; 20: 185-90. Calogero AE, De Palma A, Grazioza C, et al. High sperm aneuploidy rate in unselected infertile patients and its relationship with intracytoplasmic sperm injection outcome. Hum Reprod 2001; 16:1433-39. ORIGINAL RESEARCH EFFECT OF CHEMOTHERAPY ON THE QUALITY OF LIFE IN PATIENTS WITH LYMPHOMA 1 Esra Saatçı1, Yüksel Koçak1, Nafiz Bozdemir1, Ersin Akpınar1, Zeynep Kalaylıoğlu-Wheeler2 Çukurova Üniversitesi Tıp Fakültesi, Aile Hekimliği Anabilim Dalı, Adana, Türkiye 2Information Management Services Inc. , Rockville, MD, ABD ABSTRACT Objective: Advances in chemotherapy have significantly prolonged the survival of patients with lymphoma and a significant percentage of patients may be cured. The assessment of the quality of life in patients undergoing chemotherapy is of growing interest. The aim of this study is to assess the effect of chemotherapy on quality of life in patients with lymphoma. Methods: All patients (n=49) diagnosed with stage I lymphoma in the Cukurova University Oncology Department from June 2000 to January 2001 received a quality-of-life questionnaire (EORTC QLQ C-30) before chemotherapy and after the second cycle of chemotherapy. Results: Significant improvement during treatment was found in some of the physical activities, emotional state, relief from pain and fatigue, dyspnea, anorexia, sleep, and the global quality of life. When chemotherapy, age, gender and lymphoma type were taken into account, the most important factor influencing the global quality of life was educational status. Conclusion: The results may be used to reassure patients who are reluctant to go through chemotherapy that they are likely to experience an improved quality of life compared to their situation before the treatment. Keywords: Lymphoma, Quality of life, EORTC QLQ C-30, Turkey LENFOMALI HASTALARDA KEMOTERAPİNİN YAŞAM KALİTESİNE ETKİSİ ÖZET Amaç: Kemoterapideki gelişmeler lenfomalı hastaların yaşam sürelerini önemli derecede uzatmıştır ve önemli sayıda hasta tedavi edilebilmektedir. Kemoterapi alan hastaların yaşam kalitelerinin değerlendirilmesi giderek daha fazla ilgi çeken bir konu olmuştur. Çalışmamızın amacı, lenfomalı hastalarda kemoterapinin yaşam kalitesine etkilerini değerlendirmektir. Gereç ve Yöntem: Haziran 2000-Ocak 2001 tarihleri arasında Çukurova Üniversitesi Tıp Fakültesi Onkoloji Bilim Dalı’nda Evre I lenfoma tanısı alan 49 hastaya kemoterapi öncesinde ve 2. kür sonrasında yaşam kalitesi anketi (EORTC QLQ C-30) uygulandı. Bulgular: Fiziksel aktivitelerin bazılarında, duygusal fonksiyonlar, ağrı ve halsizlik, dispne, iştahsızlık, uyku ve global yaşam kalitesinde tedavi sırasında anlamlı iyileşme saptandı. Kemoterapi, yaş, cinsiyet ve lenfoma tipi göz önüne alındığında, global yaşam kalitesini etkileyen en önemli faktör hastanın eğitim durumuydu. Sonuç: Çalışmamızın sonuçları, kemoterapi öncesindeki yaşam kalitesine kıyasla tedavi sonrası yaşam kalitesinde iyileşme olması nedeniyle, kemoterapi alma konusunda isteksiz olan hastalara yardımcı olmada kullanılabilir. Anahtar Kelimeler: Lenfoma, Yaşam kalitesi, EORTC QLQ C-30, Adana Corresponding author: Esra Saatçı, M.D. Çukurova Üniversitesi Tıp Fakültesi, Aile Hekimliği Anabilim Dalı, Adana, Türkiye e-mail: esaatci@cu.edu.tr 98 Marmara Medical Journal 2007;20(2);98-103 Marmara Medical Journal 2007;20(2);098-103 Esra Saatçı, et al. Effect of chemotherapy on the quality of life in patients with lymphoma QOL refers to the patients' appraisal of, and satisfaction with, their current level of functioning as compared to what they perceive to be possible or ideal6. This definition resembles that of the World Health Organization (WHO): Individuals' perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns7. Quality of life is the state of well-being that is a composite of two components: the ability to perform everyday activities that reflect physical, psychological, and social well-being; and patient satisfaction with levels of functioning and control of disease8. Cella suggests that QOL comprises two components, subjectivity and 9 multidimensionality . Subjectivity refers to the fact that QOL can be understood only from the patient's perspective. Multidimensionality refers to the fact that QOL includes a wide range of dimensions which can be grouped into one of four correlated but distinct areas: physical, functional, emotional and social well-being9. Quality of life (QOL) is related to symptoms, functioning, psychological and social wellbeing, and probably to a lesser extent to meaning and fulfillment10. QOL has become a parameter of equal importance to other values characterizing the success of treatment, as important as numbers describing e.g. mean survival, disease free survival, or neoplasm controlled survival in modern oncology11. INTRODUCTION Advances in chemotherapy significantly prolong the survival of patients with lymphoma and may cure a significant percentage of these patients. However, it is well known that chemotherapy is associated with various side effects which affect the patients’ quality of life. The impact of disease and treatment on the patient’s overall well-being and functioning is a topic of growing interest in clinical research and practice1,2. Interest on assessing the quality of life (QOL) of patients with lymphoma after chemotherapy continues to grow as well. Some researchers have focused on exploring the relationship between the QOL and lymphoma treatments3,4. We designed the study presented here to investigate the effect of chemotherapy on QOL in stage I lymphoma patients. The results of this study may provide a reference while patients are making their decision on the treatment and may give them a sense of what to expect after having been exposed to the chemo treatment. The results may also be helpful to health care professionals in laying out the patient’s treatment plan. PATIENTS AND METHODS Study Subjects All of the 49 patients with stage I lymphoma in the Department of Oncology between June 2000 and January 2001 were included in the study. The patients were interviewed in the clinic at the time of the diagnosis. Informed consent was obtained and confidentiality was guaranteed. The study was approved by the Cukurova University Ethics Committee. Sociodemographic variables such as age, profession, income, education, and marital status were obtained. A quality-of-life questionnaire (European Organization for Research and Treatment of Cancer Quality of Life Core 30 [EORTC QLQ C-30]) was administered before treatment and after the completion of the second cycle of chemotherapy. The EORTC QLQ-C30 is widely employed in Europe and its validity is well established12-15. This questionnaire has a modular structure and consists of a core questionnaire EORTC QLQ-C30 (15) and additional modules which are developed specifically for cancer patients of different diagnostic groups16-19. The 30 individual items of the EORTC QLQC30 can be summarized in: (i) Function scales: physical (PF), role (RF), emotional (EF), cognitive (CF) and social (SF), (ii) Symptom scales: fatigue (FA), nausea/vomiting (NV) and pain (PA), (iii) Single-item scales: dyspnea (DY), sleep disturbance (SL), appetite loss (AP), constipation (CO), diarrhea (DI), financial Assessment of QOL There is no consensus in the literature on how to define QOL5. Cella and Tulsky stated that 99 Marmara Medical Journal 2007;20(2);98-103 Esra Saatçı, et al. Effect of chemotherapy on the quality of life in patients with lymphoma impact of the disease/treatment (FI), and a global health status/quality of life (QOL) scale. Items were scored and scales were constructed using recommended procedures19. Patients responded the questions regarding the physical functioning on a two-point scale (1= with no problem, 2= with problem) whereas they responded each question of symptom scales based on a four-point scale (from 1=not at all to 4=a lot). Questions regarding global quality of life were based on a seven-point scale (from 1=very bad to 7=very good). 0 indicates that it was collected before the chemotherapy. A p-value of less than 0.05 was considered statistically significant. RESULTS Forty-nine subjects participated in this study. Twenty six (53%) patients were female and 23 (47%) were male. Mean age was 47.1 years old with a standard deviation of 17.3 and a range between 14 and 75. The majority of the patients had intermediate educational status (28.6% illiterate, 12.2% rudimentary reading-writing skill, 38.8% grades from one to eight, 12.2% high school, and 8.2% university degree). Twenty eight (57.1%) patients had NHL (Non Hodgkin’s Lymphoma) whereas 21 (42.9%) had HL (Hodgkin’s Lymphoma). Disease duration ranged between 1-24 months (4.8±4.0). Statistical analysis The statistical analyses were carried out using Statistical Analysis Software (SAS) version 9.1 (SAS Institute Inc., Cary, NC, USA 20022003). Logistic regression was used to model the relationship between each response variable regarding the QOL and the independent variables, namely chemotherapy, sex, age, education, and lymphoma type. Cumulative logit model was used in the logistic regression analysis for each dependent variable, i.e. each component of QOL that has multiple response categories. The design of the study was “repeated measures design” as the data on QOL variables were collected from each patient once before the chemo and once after the second cycle of the chemo to monitor his or her response to the chemotherapy. The logistic regression analysis for repeated measures data was performed by employing the GENMOD procedure in SAS with the REPEATED option. The results of the analysis are presented in Tables I and II. Table I shows the coefficient estimates, p-values, and confidence intervals related with the chemotherapy effect on QOL components adjusted for age, sex, education, and lymphoma type. The level of association between the global well-being and the predictor variables are presented in Table II. As shown in Table I, in a logistic regression model adjusting for age, sex, education, and lymphoma type, chemotherapy remained a significant predictor of QOL improvement in many aspects. Participants had significantly less physical problems in terms of carrying a heavy bag and long walks (Β=0.91, p=0.02; Β=1.30, p=0.002) and they were significantly less prone to be in bed after the chemotherapy (Β=1.20, p=0.01). The chance of living an emotionally more stable life increased with chemotherapy (p=0.0004, p=0.001, p=0.003, p=0.0002, respectively). The impact of the physical condition on a lymphoma patient’s social life was significantly less severe after the chemotherapy (Β=0.77, p=0.02). The results implied that stage I lymphoma patients suffered from fatigue less after the chemotherapy (p<0.0001 for all three elements identifying the fatigue). Pain, dyspnea, sleeping, and appetite loss were significantly less of a problem after the chemotherapy (p=0.0003, p=0.02, p=0.0002, The logit of the probability of the response variable being less than a certain level (PR) was modeled as a linear function of the independent variables. That is, logit(PR) = α + Β TX where X represents the independent variables and Β represents the coefficients (i.e. logarithm of the odds ratios) of the corresponding independent variables. If a coefficient is greater than zero, the response scale tends to be smaller at higher values of the corresponding independent variable. The value of 1 for the chemotherapy dummy variable indicates that the data on the repeated measure factors was collected after the second cycle of the chemotherapy, whereas the value 100 Marmara Medical Journal 2007;20(2);98-103 Esra Saatçı, et al. Effect of chemotherapy on the quality of life in patients with lymphoma p<0.0001, respectively). Difficulty in housework was not significantly associated with chemotherapy (p=0.395, p=0.921). Similarly, chemotherapy did not have a significant effect on cognitive difficulty, nausea, vomiting, constipation, and diarrhea (p=0.057, p=0.118, p=0.214, p=0.057, p=0.676, respectively) in stage I lymphoma patients. At a given combination of sex, age, education, and lymphoma type, after the chemotherapy there was a 2.7-fold increase in the overall quality of life compared to before the chemotherapy (Β=-0.99, exp(-Β)=2.69, p=0.001). As shown in Table II, in the overall sample women were significantly more likely than men to have a better global QOL (Β=-2.08, p=0.038). Participants with a school degree were significantly more likely to have a better global QOL than the illiterate participants. The odds of a better global well-being improved as the school degree became more advanced (p=0.0001, p=0.04). Global QOL was not significantly associated with age or lymphoma type (p=0.75, p=0.073, respectively). Table 1: Effect of chemotherapy on various different functions defining the quality of life adjusted for age, education, sex, and lymphoma type (Logistic regression analysis of repeated measures data) Scales Physical Carrying a heavy bag Long walks Short walks Need to stay in bed or chair Need help with eating, dressing, washing Emotional Stress Worry Nervousness Feeling unhappy Role Difficulty with housework Completely unable to do housework Social Impact of the physical condition and treatment on social life Impact of them on the budget Impact of them on the family life Fatigue Need to rest Feeling weak Feeling tired Pain Feeling pain Interruption of daily activities by pain Cognitive Difficulty Nausea Vomiting Dyspnea Sleep problem Appetite Loss Constipation Diarrhea β: regression coefficient estimate 95% CI: 95% confidence interval β p-value 95% CI 0.91 1.30 0.67 1.20 0.30 0.019 0.002 0.312 0.012 0.468 (0.15, 1.67) (0.49, 2.11) (-0.63, 1.96) (0.26, 2.15) (-0.51, 1.10) 1.12 1.24 1.04 1.33 0.0004 0.001 0.003 0.0002 (0.50, 1.74) (0.51, 1.98) (0.36, 1.71) (0.64, 2.02) 0.32 0.03 0.395 0.921 (-0.41, 1.04) (-0.59, 0.66) 0.77 0.023 (0.11, 1.44) 0.14 -0.13 0.618 0.614 (-0.40, 0.67) (-0.65, 0.38) 1.50 1.29 1.68 <0.0001 <0.0001 <0.0001 (0.80, 2.20) (0.65, 1.92) (0.99, 2.37) 1.29 1.90 0.73 0.59 0.66 1.02 0.92 1.26 0.87 0.21 0.0003 <0.0001 0.057 0.118 0.214 0.023 0.0002 <0.0001 0.057 0.676 (0.60, 1.99) (1.17, 2.63) (-0.02, 1.48) (-0.15, 1.34) (-0.38, 1.71) (0.14, 1.89) (0.44, 1.41) (0.66, 1.85) (-0.02, 1.76) (-0.77, 1.18) 101 Marmara Medical Journal 2007;20(2);98-103 Esra Saatçı, et al. Effect of chemotherapy on the quality of life in patients with lymphoma Table II: Effect of the factors of interest and the chemotherapy on global well being. (Logistic regression analysis of repeated measures data.) Factor Chemotherapy Age Female vs. Male Basic reader and Grade 1-8 vs. illiterate High-school and university vs. illiterate Type II vs. Type I Estimate Standard Error of the coefficient -0.99 0.34 -0.004 0.01 -1.08 0.52 -1.27 0.62 p-value 95%CI 0.004 0.750 0.038 0.04 (-1.67,-0.32) (-0.03, 0.02) (-2.09,-0.06) (-2.48,-0.06) -2.43 0.63 0.0001 (-3.66,-1.20) -0.75 0.42 0.073 (-1.58, 0.07) separation) and may also be due to the increase in hope at the onset of the chemotherapy. The improvement in sleep and appetite may be due to the decrease in pain as this type of decrease leads to better sleep and better appetite. DISCUSSION We found herein that chemotherapy helped the appetite, fatigue, pain, sleep, emotional life, social functioning, and the global quality of life after the second cycle of the treatment. Our results are consistent with another study performed with the same instrument comparing the situation at the beginning of chemotherapy and at the end of inpatient treatment20. Their analyses showed that physical, emotional, and social functioning improved significantly from beginning of chemotherapy to the end of inpatient treatment. They also found that at the end of inpatient treatment, patients suffer significantly less from fatigue, nausea, loss of appetite and sleep disturbance. We examined the effect of chemotherapy on fatigue on the subgroup of subjects who were stage I Hodgkin’s lymphoma. Our finding contrasts with another study in which fatigue levels of patients with Hodgkin’s lymphoma were found to be high, even years after treatment21. The source of this inconsistency might be the differences between the fatigue questionnaires employed. The authors employed Multidimensional Fatigue Inventory to evaluate the fatigue of their study patients21. Another source might be our data lacking information on some physical and psychological factors which were shown to be the components of cancer related fatigue22,23. Cella and Tulsky stated that the patients' QOL refers to their appraisal and satisfaction with their current level of functioning compared to what they perceive to be possible or ideal6. The responses to the questionnaire may therefore give a subjective picture of the patients' possibilities of handling the physical, cognitive, emotional and social strain imposed by the disease and treatment5. Coping strategies depend on the person's internal adaptation, at an unconscious level, resulting in life satisfaction, in combination with exterior adjustment, including actions at a conscious level, resulting in well-being5. In our study, no measure was used for assessing personality aspects. This study has some limitations. Generalizations should be made carefully on the basis of the data which we gathered here due to the moderate sample size and the site of the study which was restricted to a university hospital. More extensive studies conducted over multiple centers would further elucidate the effect of chemotherapy on fatigue in lymphoma patients. In conclusion, the results of this study demonstrate that the chances of having a more stable emotional life increased with chemotherapy in stage I lymphoma patients. Also the findings in this study suggest that chemotherapy improves ability to function In our study, we observed improvement in emotional functioning after the second dose of chemotherapy. This may be due to the decrease in the distress caused by hearing the bad news and facing up to the existential issues (worries about future, death, and 102 Marmara Medical Journal 2007;20(2);98-103 Esra Saatçı, et al. Effect of chemotherapy on the quality of life in patients with lymphoma physically and socially and quality of life in stage I lymphoma patients in addition to relieving symptoms. Acknowledgments We thank Cukurova University Research Foundation for their financial support (Grant no:TF.2000.U.26), Baris Surucu (Department of Statistics, Middle East Technical University, Ankara, Turkey) for the statistical analysis, Prof. Dr. Michael Weingarten (Department of Family Practice, Tel-Aviv University, Israel), Harry S. Shannon and Lauren Griffith (Program in Occupational Health and Environmental Medicine, McMaster University, Canada) for the critical reading of the paper, Prof. Dr. Semra Paydas and Prof. Dr. Berksoy Sahin (Department of Oncology, Cukurova University, Adana, Turkey), Prof. Dr. Refik Burgut (Department of Biostatistics, Cukurova University, Adana, Turkey), and our patients for their support and contribution. 12. 13. 14. 15. 16. REFERENCES 1. Guyatt G, Veldhuyzen Van Zanten S, Feeny D, Patrick D. Measuring quality of life in clinical trials: a taxonomy and review. Can Med Assoc J 1989; 140: 1441-1448. 2. Lauper P, Versteegen U. The importance of quality of life in policy decisions: new end points in medical outcome assessment. Pharm Med 1992; 5: 43-50. 3. Schumacher A, Kessler T, Riedel A, Buchner T, van de Loo J. Quality of life and coping with illness in patients with acute myeloid leukemia. Psychother Psychosom Med Psychol 1996; 46: 385-390. 4. 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A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer 2000; 36: 17961807. Blazeby JM, Alderson D, Winstone K, et al. Development of an EORTC questionnaire module to be used in quality of life assessment for patients with oesophageal cancer. The EORTC Quality of Life Study Group. Eur J Cancer 1996; 32A: 1912-1917. Sprangers MA, Cull A, Groenvold M, Bjordal K, Blazeby J, Aaronson NK. The European Organization for Research and Treatment of Cancer approach to developing questionnaire modules: an update and overview. EORTC Quality of Life Study Group. Qual Life Res 1998; 7: 291-300. Schumacher A, Kessler T, Buchner T, Wewers D, van de Loo J. Quality of life in adult patients with acute myeloid leukemia receiving intensive and prolonged chemotherapy-a longitudinal study. Leukemia 1998; 12: 586-592. Ruffer JU, Flechtner H, Tralls P, et al. Fatigue in longterm survivors of Hodgkin‘s lymphoma; a report from the German Hodgkin Lymphoma Study Group (GHSG). Eur J Cancer 2003; 39: 2179-2186. Vogelzang NJ, Breitbart W, Cella D, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 1997; 34: 4-12. Curt GA. The impact of fatigue on patients with cancer: overview of FATIGUE 1 and 2. Oncologist 2000; 5 (Suppl 2): 9-12. ORIGINAL RESEARCH THE IMPACT OF THE WOMEN’S HEALTH INITIATIVE STUDY ON THE INITIATION AND CONTINUATION OF HORMONE THERAPY IN A TERTIARY MENOPAUSE UNIT IN TURKEY Mithat Erenus, Meltem Uygur, Pınar Yörük, Fatih Durmuşoğlu Marmara Üniversitesi, Kadın Hastalıkları ve Doğum ABD, İstanbul, Türkiye ABSTRACT Objective: To determine the initiation and continuation rate of hormone therapy (HT) following publication of the Women’s Health Initiative (WHI) study. Methods: A survey was performed on 816 postmenopausal women between July 2002 and July 2005. Questions included sociodemographic characteristics, determinants of HT, use of knowledge and source of information regarding the WHI study. Results: The average age was 49,3±3,6 years. Among the participants 22,1% were using HT whereas 77,9% were not . Of the women; 131, 99, 60, 157 were graduated from university, high school, middle and primary school respectively. HT usage was 25% among primary school and 20% among university graduates, which appeared not to be affected by educational level. The rate of starting HT was 18,6% in the second half of 2002. Initiation of HT was 30,5% in 2003, than decreased to 21,5% in 2004 and 20,9% in 2005. Among women for whom HT was initiated after WHI, the continuation rate was 41%. Conclusion: Our survey showed the negative impact of WHI findings on both about the initiation and continuation of HT in our menopause unit in Turkey. Information was mainly obtained through the media or physician, may well have an important impact on the continuation or discontinuation of HT. Keywords: Hormone treatment, WHI, Menopause TÜRKİYEDE TERSİYER BİR MENOPOZ MERKEZİNDE WOMEN’S HEALTH İNİTİATİVE ÇALIŞMASININ HORMON TEDAVİSİ DEVAMI VEYA KESİLMESİNE OLAN ETKİSİ ÖZET Amaç:Women’s Health Initiative (WHI) çalışmasının yayınlanmasının takiben hormon tedavisinin (HT) sürdürülmesi veya kesilmesine olan etkisini incelemek. Materyal ve Metod: Çalışma Temmuz 2002 ile Temmuz 2005 tarihleri arasında 816 postmenopozal kadın ile gerçekleştirildi. Hastalara sosyo-demografik özellikleri, HT kullanım bilgileri, WHI çalışması hakkında bilgiler soruldu. Bulgular: Kadınların ortalama yaşları 49,3±3,6 ve cevap oranları %54,7 idi. Katılımcıların %22,1'i HT almakta iken, %77,9'i HT kullanmamaktaydı. Kadınların üniversite mezunu, lise, ortaokul ve ilkokul mezunu olanları sırasıyla 131, 99, 60, 157 şeklinde idi. İlkokul mezunlarında HT kullanım oranı %25,üniversite mezunlarında %20 olması tedavinin eğitim durumundan etkilenmediğini göstermekte idi. 2002 yılının ikinci yarısında HT başlama oranı 18,6%, 2003'te % 30,5 şeklinde olup 2004 yılında %21,5'e, 2005 yılında %20,9 oranına geriledi. WHI çalışmasından sonra HT başlanan kadınlarda tedaviye devam oranı %41'di. Sonuç: Çalışmamız WHI sonuçlarının menopoz ünitemize HT devamı ve kesilmesi üzerine etkide bulunduğunu göstermektedir. WHI hakkında bilginin en çok medyadan veya doktorlardan elde edildiği ve HT devamı veya kesilmesi üzerine belirgin etkisi olduğu saptandı. Anahtar Kelimeler: Hormon tedavisi, WHI, Menopoz Corresponding author: Meltem Uygur, M.D. Marmara Üniversitesi,Tıp Fakültesi Hastahanesi, Kadın Hastalıkları ve Doğum ABD, Altunizadde, İstanbul, Türkiye e-mail: meltemu@yahoo.com 104 Marmara Medical Journal 2007;20(2);104-109 Marmara Medical Journal 2007;20(2);104-109 Mithat Erenus, et al. The impact of women’s health initiative study on initiation and continuation of hormone therapy in a tertiary menopause unit in turkey and continuation of HT following the publication of the WHI study. INTRODUCTION Menopause is a time of great psychological and physiological change and many women report symptoms such as hot flushes that negatively affect their quality of life. Hormone therapy was offered to almost all postmenopausal women to relieve the symptoms in the short term and as a preventive medicine in the long term. In 1995, approximately 38% of postmenopausal women in the USA were taking hormone therapy (HT)1. Several observational studies had suggested that HT offered women some protection against coronary heart disease and osteoporosis2-5. More recently, 2 large randomized clinical trials, The Heart and Estrogen / Progestin Replacement Study (HERS)6 and the Women’s Health Initiative (WHI) have been published7. These clinical trials demonstrate that the risks associated with HT outweigh the benefits for women. The studies found an association between prolonged use of HT and increased risk of breast cancer, thromboembolism and infarctions. Widespread coverage of the study results by media and professional journals raised concerns among the public health care providers and particularly among women using postmenopausal HT. Many women stopped treatment abruptly because of the global panic which was related to health concerns8-9. Thus in the post WHI era, compliance seems to be largely influenced by fears expressed by both medical personnel and the public. The lay press also provided wide coverage on this issue. Time Magazine in its July 2002 issue published a cover article entitled as “Truth about Hormones” and claimed that women were confused with the new information10. PATIENTS AND METHODS We performed a survey on 816 postmenopausal women who presented to Marmara University Menopause Unit in Istanbul between July 2002 and July 2005. Menopause is defined as the cessation of menstruation for at least 12 months or serum FSH levels > 40 mIU/ml. Women who had undergone hysterectomy with bilateral oophorectomy were defined as surgically menopausal. Surveys were performed by two physicians (PY,MU) who worked at the menopause unit by either direct interview or phone calls. Our questionnaire addressed sociodemograhic characteristics including present age, age at menopause, body mass index (BMI), educational status, as well as determinants of HT use, knowledge and source of information regarding the WHI study. We aimed to obtain information about women’s attitudes regarding HT use and reasons to continue or discontinue use of HT. Women were also asked if they had been provided with information about the risks and benefits of HT and about the source of their information. The study has been approved by the ethical committee. The variables were compared with chi-square test and student’s t test where appropriate and p < 0.05 was regarded as statistically significant. The results were interpreted by using the SPSS 12.0 (SPSS, Inc, Chicago, IL, U.S.A) program. RESULTS In total, 816 women were asked to participate in this study. The response rate was 54.7%. Thus 447 women were included in the analysis. In Turkey the scientific and public debate about the results of WHI is still ongoing and influencing the initiation and continuation of HT in postmenopausal women. The sociodemograhic characteristics of the women are shown in table I. The mean age at presentation was 49.3± 3.6 years with a range of 44-62 years. A total of 396 (88.6%) women were natural and 51 (11.4%) women were surgical menopausal women. Among the We conducted a survey to evaluate the perception of the WHI results among women who present to our tertiary menopause unit. The objective was to determine the initiation 105 Marmara Medical Journal 2007;20(2);104-109 Mithat Erenus, et al. The impact of women’s health initiative study onthe initiation and continuation of hormone therapy in a tertiary menopause unit in Turkey participants of the survey, 22.1% (99/447) were using HT wheras 77.9% (348/447) were not using HT. Body mass index (BMI) was similar between HT user and nonuser with a mean value as 26.7±3.8. Continuous combined HT regimen was used by 73.7% (73/99) of women and sequential HT was used by 26.3% (26/99) of HT users. HT usage was significantly higher among surgically menopausal women (66% (34/51)) than among natural menopausal women (20% (81/396)) (p<0.05). HT users were younger than non-users (48.6±2.4 vs 49.4±2.3 respectively and this difference was statistically significant (p<0.01). respectively. The educational status of women were defined as high in 49% (230/447) and low in 51% (217/447) accordingly. HT usage was not significantly affected by educational level (p>0.05). The rate of HT use among primary school and university graduates was 25% and 20% respectively. Women were categorized according to the reasons for attendance to our clinic between July 2002 – July 2005. The most common reason was routine control with a rate of 66,99% (295/447), followed by 27,06% (121/447) with vasomotor symptoms. Osteoporotic and urogenital complaints were mentioned by 6,04% (27/447) and 0,89% (4/447) of the women respectively. The educational level was categorized as primary, middle, high school and university graduates.Primary-middle school graduates were defined as having low educational status (LES) and high school-university graduates were defined as having high educatinal status (HES). Of the participating women 131, 99, 60, 157, women were university, high school, middle school and primary school graduates Among the postmenopausal women who attended our clinic, the rate of starting HT was 18,6% in the second half of 2002 immediately after the publication of the study. In 2003 initiation of hormone use was 30,5%, than decreased to 21,1% in 2004 and 20,9% in 2005. Table 1: Demographic characteristics of the study. Total HT users non-HT users Age mean 49.3 ± ± SD 2.3 mean 48.6 ± ± SD 2.4 mean 49.4 ± ± SD 2.3 p value p < 0,001 BMI 26.7 ± 3.8 26.7 ± 4.2 26.7 ± 3.6 p > 0,05 n (%) n (%) n (%) p value 396 51 88.6 11.4 82 17 21 33 314 34 79 67 157 60 99 131 447 35.1 13.4 22.2 29.3 100 41 9 22 27 99 41.4 9.1 22.2 27.3 100 116 51 77 104 348 33.3 14.7 22.1 29.9 100 Menopause Natural Surgical Educational Status Primary school Middle school High school University degree Total HT: hormone treatment, BMI : body mass index 106 p > 0,05 p > 0,05 p > 0,05 p > 0,05 Marmara Medical Journal 2007;20(2);104-109 Mithat Erenus, et al. The impact of women’s health initiative study onthe initiation and continuation of hormone therapy in a tertiary menopause unit in Turkey Table II: Main reasons given for discontinuation of hormone treatment. Reason Number of subjects Fear of cancer Decreasing vasomotor symptoms Weight gain Bleeding complaints Other Total 46 (46,4%) 36 (36,3%) 10 (10,1%) 5 (5,0%) 3 (3,0%) 99 (100%) Women for whom HT was initiated after the WHI study publication, the continuation rate of treatment was 41%. The continuation rate of HT was 54% (54/99) in 2002, 31% (31/99) in 2003, 21% (21/99) in 2004 and 16% (16/99) in 2005. The reasons for discontinuation of HT were categorized in five groups, shown in table II. Women discontinued therapy mostly because of fear of cancer 46,4% (46/99), decreasing vasomotor symptoms 36,3% (36/99), weight gain 10,1% (10/99), bleeding complaints 5,0% (5/99) and other reasons 3,0% (3/99). past observational studies were consistent in indicating a positive impact for cardiovascular disease, lipid and carbohydrate metabolism, and bone health2-5. Furthermore, encouraging information was noted in studies of Alzheimer disease although evidence was inconclusive11. However, the evidence from randomized trials challenged our prior beliefs and management. The HERS study found a 50% increase in cardiac events in the first year of hormone therapy use among women with established coronary heart disease6. This trend was supported in the WHI with increased risk for coronary heart disease7. Furthermore, the WHI results indicated an increased risk for breast cancer, stroke and pulmonary embolism. Although there were protective effects against hip and vertebral fractures and colorectal cancer, the overall risks were considered to outweigh the benefits. Widespread media attention to the WHI trial results may have resulted in comparable dissemination of this information across diverse socioeconomic groups. A variety of studies from different countries showed HT discontinuation rates and the changing approach to HT after the WHI study results. Travers et al and Clanget et al claimed that there was a significant decrease in HT usage years after the WHI study in Australia and Germany12-13. Buist et al stated a rapid decline in HT use including 100.000 women14. Leung et al reported a 43,5% decline in prescribing conjugated equine estrogens and its related products after the second half of 2002 in Women were questioned to assess their knowledge about the WHI study. Of the participants, 51,7% (231/447) obtained knowledge through the media, 23% (103/447) received information from a physician, 21,3% (95/447) from friends and 4% (18/447) could not remember the study and its conclusions . Furthermore, when the current opinion of the participants about HT was questioned, 47,4% (212/447) of the women had concerns of cancer, 21,7% (97/447) of women found HT useful for vasomotor symptoms, 10,3% (46/447) of women believed that HT was effective for the prevention of osteoporosis and 16,6% (74/447) of the women stated that HT was benefical for the cardiovascular system whereas 4% (18/447) of the women did not have an opinion. DISCUSSION The last decade has witnessed a dramatic shift in the evidence on the use of hormone treatment by postmenopausal women. The 107 Marmara Medical Journal 2007;20(2);104-109 Mithat Erenus, et al. The impact of women’s health initiative study onthe initiation and continuation of hormone therapy in a tertiary menopause unit in Turkey Hong Kong15. Blümel et al found a 8,6% drop in all hormone prescriptions for menopause in Chile16. Both of these studies pointed out changes in the attitudes of gynecologists as well as in patients’ attitudes. Heitmann et al reported that the most common reason for stoppping HT was the higher risk benefit ratio (54%)17. continuation rate after the WHI study publication, which overlaps with the rate of women who started HT because of their vasomotor symptoms in our previous study18. Indeed our results showed that 51,7% of the participants obtained knowledge about the WHI from the media whereas only 23% received information from physicians. The physician as source of information may well be associated with the total HT use rate of the participants of our survey (22,1%). Hoffman et al found that the most frequent source of information on HT was newspapers or magazines (43,8%) and television or radio (31,7%)21. The declined rate of starting HT, after the WHI study in our menopause unit, was most probably due to media influence which appears to be independent of educational status. A couple of years prior to the WHI study publication, we reported 71,2% continuation rate in our tertiary menopause unit18. The educational status of the patients was related to starting HT but was not related to the discontinuation of HT. Bleeding episodes and fear of cancer were the 2 most common reasons for discontinuation of treatment. In the present study, similar to our previous data, the discontinuation of HT was not affected by educational status and fear of cancer was a common reason to stop treatment. On the contrary, in the present survey after the WHI study, we did not find any relation between education level and starting HT. Populations were influenced at different times after publication of the clinical trials. Haas et al reported that before publication of the randomized trial results, HT usage was increasing at 1% per quarter and after publication of the HERS study, HT usage decreased by 1% per quarter22. After publication of the WHI study, usage declined by 18% per quarter22. Kim et al found the decreasing time as 3 months and pointed out that trial results can have a rapid effect on practice23. In a study by Ettinger et al, discontinuation of HT was 56% 6-8 months after the WHI findings, despite not being well informed24. In the present study, the decrease in HT use was most significant in the 6 months following the WHI (18.6%), although relatively increased in the consecutive years. In the present study, the initiation of hormone treatment was 18,6% which is lower than our previous 60% rate (unpublished data). Our data indicated an increased HT initiation rate among our patients in 2003. This increase was most probably due to group counseling, meetings performed by senior counselors in order to inform patients about WHI study results at the end of the year 2002. In the following years the rate of initiation of HT declined to 21%. In our survey the continuation of HT was found to be 41% after the WHI publication. This rate was lower than in our previous 2 studies before the WHI 18,19. We first reported 71,2% continuation rate in 1998 and 71,7% continuation rate after 2 years in 2001. The current consensus is that HT should be reserved for the treatment of menopausal symptoms at the lowest effective dose for the shortest duration. After the WHI study publication, in the light of the North American Menopause Society (NAMS) guidelines, we preferred to individualize HT in postmenopausal 20 women . We mostly started HT for women who had vasomotor symptoms. Our previous data indicated that the reason for taking HT was vasomotor symptoms in 42% of the patients18. In the present study, we found 41% Deciding about starting or stopping HT requires a comprehensive discussion between the physician and the patient regarding benefits and risks. The source of information about HT, either media influence or physician’s advice, may have an important impact on continuation or stopping HT. Ultimately the decision to start and continue 108 Marmara Medical Journal 2007;20(2);104-109 Mithat Erenus, et al. The impact of women’s health initiative study onthe initiation and continuation of hormone therapy in a tertiary menopause unit in Turkey 13. Clanget C, Hinke V, Lange S, et al. Patterns of hormone replacement therapy in a population-based cohort of postmenopausal German women. Changes after HERS II and WHI. Exp Clin Endocrinol Diabetes 2005;113:529-533. 14. Buist DSM, Newton KM, Miglioretti DL, et al. Hormone therapy prescribing patterns in the United States. Obstet Gynecol 2004;104:1042-1050. 15. Leung KY, Ling M, Tang GW. Use of hormone replacement therapy in the Hong Kong public health sector after the Women’s Health Initiative trial. Maturitas 2005;52(3-4):277-285. 16. Blümel JE, Castelo-Branco C, Chedraui PA, et al. Patient’s and clinician’s attitudes after the Women’s Health Initiative study. Menopause 2005;11:57-61. 17. Heitmann C, Greiser E, Dören M. The impact of the Women’s Health Initiative Randomized Controlled Trial 2002 on perceived risk communication and use of postmenopausal hormone therapy in Germany. Menopause 2005;12:405-411. 18. Karakoç B, Erenus M. Compliance considerations with hormone replacement therapy. Menopause 1998;5:102106. 19. Erenus M, Karakoc B, Gurler A. Comparison of effects of continuous combined transdermal with oral estrogen and oral progestogen replacement therapies on serum lipoproteins and compliance. Climacteric 2001;4:228234. 20. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: Position statement of the North American Menopause Society. Menopause 2004;11:11-33. 21. Hoffmann M, Hammar M, Kjellgren KI, et al. Changes in women’s attitudes towards and use of hormone therapy after HERS and WHI. Maturitas 2005;16;52:1117. 22. Haas JS, Kaplan CP, Gerstenberger EP, Kerlikowske E. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results. Ann Intern Med 2004;140(3):184-188. 23. Kim N, Gross C, Curtis J, et al. The impact of clinical trials on the use of hormone replacement therapy. A population-based study. J Gen Intern Med 2005;20:1026-1031. 24. Ettinger B, Grady D, Tosteson AN, et al. Effect of the Women’s Health Initiative on women’s decisions to discontinue postmenopausal hormone therapy. Obstet Gynecol 2003;102:1225-1232. HT is up to individual women and is made on the basis of the information she receives from her physician and from the media. REFERENCES 1. Keating NL, Cleary PD, Rossi AS, et al. Use of hormone replacement therapy by postmenopausal women in United States. Ann Intern Med 1999;130:545553. 2. Lobo RA. Benefits and risks of estrogen replacement therapy. Am J Obstet Gynecol 1995;173:982-990. 3. Cauley JA, Seeley DG, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122:9-16. 4. Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044-1049. 5. Gardy D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016-1037. 6. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-613. 7. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. 8. Beral V, Banks E, Reeves G. Evidence from randomized trials on the long term effects of hormone replacement therapy. Lancet 2002;360:942-944. 9. Tattersall MH. Risks and benefits of postmenopausal combined hormone replacement therapy. Med J Aust 2002;177:173-174. 10. Gorman C, Park A. The truth about hormones. Time. Health and Medicine Section. July 22, 2002. 11. LeBanc ES, Janowsky J, Chan BK, Nelson HD. Hormone replacement therapy and cognition: systematic review and metanalysis. JAMA 2001;285:1489-1499. 12. Travers C, O’Neill SM, Khoo SK, King R. Hormones down under: hormone therapy use after the Women’s Health Initiative. Aust N Z J Obstet Gynaecol 2006; 46:330-335. 109 CASE REPORT COLLOID CYST WITH SEPTUM PELLUCIDUM AGENESIS: A CASE REPORT AND REVIEW OF THE LITERATURE Deniz Konya1, Arzu Gerçek2, Serdar Özgen1, M. Necmettin Pamir1 Department of Neurosurgery, School of Medicine, Marmara University, Istanbul, Turkey 2 Department of Anesthesiology and Reanimation, Institute of Neurological Sciences,Marmara University, Istanbul, Turkey 1 ABSTRACT A 37-year-old man was admitted to our clinic with sudden onset of severe headache and vomiting. Fundoscopic ophthalmic examination revealed papiledema as a sign of increased intracranial pressure. Cranial magnetic resonance imaging revealed homogenous gadolinium, enhanced cystic lesion in the third ventricle and agenesis of the septum pellucidum. Transcallosal interhemispheric approach was performed and the cystic lesion was excised totally. Pathological diagnosis was a colloid cyst. After one-day in intensive care, the patient was discharged on postoperative day 4. His neurological examination was normal after a six-month follow-up. This report represents the second report of colloid cyst and septal agenesis, and a first report of treatment of the colloid cyst with this syndrome. Keywords: Colloid cysts, Septum pellucidum agenesis, Treatment modality SEPTUM PELLUCİDUM AGENEZİNİN EŞLİK ETTİĞİ KOLLOİD KİST: VAKA SUNUMU VE LİTERATÜR TARAMASI ÖZET 37 yaşında erkek hasta ani başlayan şiddetli başağrısı ve kusma şikayetleri ile kliniğimize başvurdu. Gözdibi muayenesinde intrakraniyal basınç artışının bir bulgusu olarak papilödem saptandı. Kraniyal magnetik rezonans görüntülemede 3. ventrikülde, gadolinyum tutan kistik lezyon ve septum agenezi saptandı. Transkollazal interhemisferik yaklaşımla kist tamamen çıkarıldı. Patoloji olarak kolloid kist tanısı kondu. Yoğun bakımda bir gün takip edilen hasta, postoperatif 4 günde taburcu edildi. Altıncı ayda yapılan kontrolünde nörolojik muayenesi normal sınırlarda bulundu. Bu vaka literatürdeki 2. kolloid kist ve septal agenezis vakası ve ilk intrakraniyal basınç artışı ile bulgu veren vaka sunumudur. Anahtar Kelimeler: Kolloid kist, Septum pellusidum agenezi, Tedavi yaklaşımı they may lead to sudden neurological deterioration and death. INTRODUCTION Colloid cysts (CC), having a fibrous epithelial shaped capsule and insert mucous or hyaloids substance, account for 0.3-2 % of intracranial tumors1. They are benign tumors that can be surgically cured. They are mostly located in the anterosuperior portion of the 3rd ventricle and rarely, in the septum pellucidum1. They may block the outflow pathways, especially at foramen Monro, for the cerebrospinal fluid, causing acute hydrocephalus2. If untreated, Septum pellucidum (SP) separates the left and right lateral ventricle from each other and is made up of two thin sheets of mostly gliallike elements that have a potential space between them3. It consists of an ependymal lining toward the ventricles and contains neuronal and glial cell elements. These cell elements have connections to the hypothalamus and the hippocampus. Rakic Corresponding author: .Deniz Konya, M.D. Department of Neurology, School of Medicine, Maarmara University, Altunizade, Istanbul, Turkey e-mail: drdkonya@hotmail.com 110 Marmara Medical Journal 2007;20(2);110-113 Marmara Medical Journal 2007;20(2);110-113 Deniz Konya, et al Colloid cyst with septum pellucidum agenesis: a case report and review of the literature and Yakovlev4 suggested that the layers of septum form as a result of cavitation of the medial inferior commissural plate during the formation of corpus callosum. The two layers of SP are separate at birth. In most people, they typically start fusing posteriorly.In case of absence of the SP, the frontal horns if not distorted by a cleft, have a square appearance5. Craniotomy was scheduled. Transcallosal interhemispheric approach was performed, and the tumor was excised totally (Fig. 2). Pathological diagnosis was CC. After one day in intensive care, the patient was discharged on postoperative day 4. SP agenesis may be primary or secondary to hydrocephalus. In cases with other accompanying neurological disorders, SP agenesis can be detected in childhood. This report represents the second report of CC and septal agenesis, and a first report of treatment of CC with this syndrome. CASE REPORT A 37-year-old man presented with sudden onset of severe headache and vomiting. His consciousness progressed to stupor. Fundoscopic ophthalmic examination revealed papiledema as a sign of increased intracranial pressure. Cranial magnetic resonance imaging (MRI) revealed a homogenous, gadolinium enhanced cystic lesion in the third ventricle and agenesis of the septum pellucidum (Fig.1). The results of laboratory studies were within reference values. Figure 2: Postoperative T1 weighted coronal cranial MRI. Colloid cyst was excised totally. DISCUSSION The human brain is divided into two hemispheres by the septum or septum verum. The septum verum is a combination of nerve cells and the SP6. The evolution of both the SP and the corpus callosum is the same. However, SP anomalies may accompany corpus callosum anomalies. The well-known anomalies of the SP are cavum SP, cavum verge cysts and agenesis of the SP. Septooptic displasia, schizencephaly, corpus callosum agenesis, hydrocephalus, porencephaly, basal encephalosel and hydrancephaly are usually associated with SP anomalies7. The SP is a part of the limbic system. Thus, limbic system anomalies may also be accompanied by SP anomalies. Schizophrenia is frequently seen with SP agenesis because of the relation with the limbic system6. Our patient’s psychological status was previously normal. Congenital hemiplegia or diplegia is another entity that may occur in SP agenesis and porencephaly. Figure 1: Preoperative T1 weighted coronal cranial MRI demonstrates homogeneous contrast enhanced colloid cyst (black arrows) ventricular enlargement and septum pellucidum agenesis. 111 Marmara Medical Journal 2007;20(2);110-113 Deniz Konya, et al Colloid cyst with septum pellucidum agenesis: a case report and review of the literature Barkovich and Norman8 reviewed 35 patients with SP agenesis. These patients were divided into seven groups: septo-optic dysplasia, schizencephaly, holoprosencephaly, agenesis of the corpus callosum, chronic-severe hydrocephalus, basilar encephaloceles, and porencephaly/hydrancephaly. They concluded that the absence of SP could provide a valuable clue to the diagnosis of malformations of the brain. Sargon et al9 have reported 5-layer durameter and agenesis of SP and corpus callosum in a 55-year-old man postmortem. Menezes et al7 studied 12 patients with absence of the SP associated with porencephalies. Literature reveals only one report of SP agenesis without additional malformation10. In this case, there were no other brain anomalies except SP agenesis. Gorlin’s syndrome having unusual findings of thin corpus collosum and colloid cyst. A colloid cyst is easily detected by cranial MRI and Computed tomography because of its localization, shape, or structure. Contrast enhancement is rarely seen on computed tomography, and the cyst is usually isodense or hyperdense, less frequently hypodense with cerebrospinal fluid. The density of a colloid cyst is dependent on the increases in viscosity16. The density of the cyst is important in planning the surgery. Stereotactic approach or endoscopic procedures should not be the choice for highly viscose cysts. A colloid cyst may present hypointensity, isointensity or hyperintensity in T1 sequence MRI. These appearances of colloid cysts depend on the amount of blood, hemosiderin, cholesterol crystals, cerebrospinal fluid, and paramagnetic ions in the cysts16. The most common appearence is a mass that is hyperintense on T1 and hypointense on T2 weighted studies. A colloid cyst located in the third ventricle was first described by Wallman11 in 1858 postmortem of a patient having incontinence and gait disturbance. Developmental midline cysts constitute a separate entity and are usually associated with malformation disorders of the brain. Embryologic origins of the colloid cysts are still unclear. Recently, immunohistochemical and ultrastructural trials convinced scientists that the colloid cyst has endodermal structure. Ectopic endodermal elements are supposed to migrate into the velum interpositum during central nervous system development12. The cyst contains collagen and fibroblast and is surrounded by a simple or pseudo capsule. The highly vascular collagen capsule contains hemosiderin and calcium. Colloid cysts are usually gelatinous, viscoid, or semisolid and rarely contain liquid13. In this case, the cyst was mucous. There are several considerations for the treatment of CC. Ventriculoperitoneal shunting, stereotactic cyst aspiration, neuroendoscopic surgery, transcorticaltranscallosal approach, and anterior transcallosal microsurgery are all treatment procedures for the colloid cyst1,13,16-21. The posterior transcallosal approach was first used for the colloid cyst by Dandy22 in 1921. Camacho18 recommends no intervention in the absence of hydrocephalus and a cyst size of less than 15 mm diameter, which is opposed by many authors because of the risk of sudden death1,2,16,23. In our case, total excision was achieved by anterior transcallosal approach without neurological deficit. Del Carpio et al14 reported a colloid cyst of the third ventricle with agenesis of the corpus callosum. They concluded that a colloid cyst, generally a tumor with an origin of maldevelopment, was the initiating cause of callosal agenesis. Its location, anteroinferior to the foramen Monro, coincides with that of the first callosal fibers and if present during the critical period of embryogenesis, may preclude the formation of the CC. Kantarci et al15 described a 22-year-old man with REFERENCES 1. 2. 3. 112 Laidlaw J, Kaye AH. Colloid cysts, In: Kaye AH, Laws ER Jr, eds. Brain Tumors. New York: Churchill Livingstone, 2nd ed, 2001:983-996. Antunes JL. Masses of the third ventricle. In: Wilkins RH, Rengachary SS, eds. Neurosurgery. New York: McGraw-Hill, 1985:935-993. Barkovich AJ, Norman D. Absence of the Septum Pellucidum: A useful sign in the diagnosis of congenital brain malformation. Am J Roentgenol 1989;152:353360. Marmara Medical Journal 2007;20(2);110-113 Deniz Konya, et al Colloid cyst with septum pellucidum agenesis: a case report and review of the literature 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Rakic P, Yakovlev PI. Development of the corpus callosum and cavum septi in man. J Comp Neurol 1968;132:45-72. Peraud A, Illner A, Rutka JT. Intraventricular congenital lesions and colloid cysts. Neurosurg Clin N Am 2003;14:607-619. Supprian T, Sian J, Heils A, Hofmann E, Warmuth-Metz M, Solymosi L. Isolated absence of the septum pellucidum. Neuroradiology 1999;41:563-566. Menezes L, Aicardi J, Goutieres F. Absence of the septum pellucidum with porencephalia. A neuroradiologic syndrome with variable clinical expression. Arch Neurol 1988;45:542-545. Sargon MF, Brohi RA, Ozeksi P, Tonak AK, Cumhur M. Agenesis of the corpus callosum and septum pellucidum together with a multiple layered duramater. Neuroanatomy 2002;1:2-4. Cihangiroglu M, Bulut S, Yilmaz S. Isolated septum pellucidum agenesis in an adult. J Neuroimaging 2002;12:89-91. Wallman H. Eine colloidcyste im dritten Hirnventrikel und eine lipom im Plexus choroides. Virchow's Arch (Pathol Anat) 1858;11:385–388. Tortori-Donati P, Rossi A, Biancheri R. Hydrocephalus, cysts, and other disorders of the cerebrospinal fluid spaces. In: Tortori-Donati P, ed. Pediatric Neuroradiology Brain. Berlin: Heidelberg, 2005:981982. Carmel PW. Brain tumors of disordered embryogenesis. In: Youmans JR, ed. Neurological Surgery. Philadelphia: WB Saunders, 4th ed. 1996:2761-2781. del Carpio-O’Donovan R, Cardinal E. Agenesis of the corpus callosum and colloid cyst of the third ventricle: Magnetic resonance imaging of an unusual association. Can Assoc of Radiol J 1990;41:375-379. 14. Kantarci M, Ertas U, Alper F, et al. Gorlin’s syndrome with a thin corpus callosum and a third ventricular cyst. Neuroradiology 2003;45:390-392. 15. Kondziolka D, Lunsford LD. Stereotactic management of colloid cysts: factors predicting success. J Neurosurg 1991;75:45-51. 16. Abernathey CD, Davis DH, Kelly PJ. Treatment of colloid cysts of the third ventricle by stereotaxic microsurgical laser craniotomy. J Neurosurg 1989;70:525-529. 17. Camacho A, Abernathey CD, Kelly PJ, Laws ER Jr. Colloid cysts: experience with the management of 84 cases since the introduction of computed tomography. Neurosurgery 1989;24:693-700. 18. Hall WA, Lunsford LD. Changing concepts in the treatment of colloid cysts. An 11-year experience in the CT era. J Neurosurg 1987;66:186-191. 19. Mathiesen T, Grane P, Lindquist C, von Holst H. High recurrence rate following aspiration of colloid cysts in the third ventricle. J Neurosurg 1993;78:748-752. 20. Symon L, Pell M. Surgical techniques in the management of colloid cysts of the third ventricle. The transcortical approach. In: Symon L, ed. Advances and Technical Standards in Neurosurgery. Wien: SpringerVerlag, 1990:121-133. 21. Dandy WE. Benign tumors in the third ventricle of the brain: Diagnosis and Treatment. Springfield: Charles C Thomas, 1933. 22. Yasargil MG, Sarioglu AC, Adamson TE, Roth P. Surgical techniques in the management of colloid cysts of the third ventricle. The interhemispheric-transcallosal approach. In: Symon L, Calliauw L, Cohadon F, eds. Advances and Technical Standards in Neurosurgery. Wien: Springer-Verlag, Vol 17, 1990:133-143. 23. Yasargil MG. Microneurosurgery. Stuttgart: Georg Thieme Verlag, Vol 4B, 1996:329- 342. 113 CASE REPORT ANEURYSM OF THE POPLITEAL ARTERY: CASE REPORT Atike Tekeli1, Selim Isbir2, Koray Ak2, Ali Civelek2, Yasar Birkan2, Taylan Adademir2, Nazan Atalan1, Sinan Arsan2 1 Academic Hospital, Marmara University Foundation, Cardiovascular Surgery, Istanbul, Turkey 2Marmara University,School of Medicine, Cardiovascular Surgery, Istanbul, Turkey ABSTRACT Popliteal artery aneurysms lead to many dreadful conditions if left untreated. We report a case of a 63-yearold man who presented with a pain in the lower extremity as a result of a popliteal artery aneurysm. He underwent surgery through a posterior approach with saphenous vein graft interposition. The presentation, investigation and treatment of this condition is discussed. Keywords: Popliteal artery , Aneurysm, Management POPLİTEAL ARTER ANEVRİZMASI: VAKA SUNUMU ÖZET Popliteal arter anevrizmalarının tedavi edilmediğinde birçok istenmeyen duruma neden olduğu bilinmektedir. Popliteal arter anevrizması nedeni ile alt ekstremite ağrısı ile başvuran 63 yaşındaki bir hastaya posterior yaklaşım ile safen ven interpozisyonu uygulanmıştır. Hastalığın tanısı ve tedavisi bu vaka sunumunda tartışılmaktadır. Anahtar Kelimeler: Popliteal arter, Anevrizma,Tedavi INTRODUCTION CASE REPORT The popliteal artery is the most common site for aneurysm formation among the peripheral arteries1. A popliteal artery aneurysm (PAA) mostly affects elderly men, and atherosclerosis plays a major role in the etiopathophysiology of this disease2,3. Management of PAA requires a great concern. It is known that when PAAs are left untreated, the risk of complications increases and the patients may encounter many dreadful situations, the worst being limb loss3,4. A 63-year-old man was admitted to our institution with right lower limb pain of two months aggravated by walking and edema. There was no prior history of claudication. He had previously been seen by an orthopedic surgeon for his symptoms. Analgesic treatment and a simple knee brace were recommended. However, the patient’s symptoms persistent for another month and he was then referred to our clinic. Digital substraction angiography of the lower extremities was performed. This examination revealed a PAA with a diameter of 40x34 mm (Fig. 1) and the patient was scheduled for surgery. Doppler ultrasonography was performed to control the abdominal aorta and The objective of this report is to present a case of a PAA and review the recent literature about the diagnosis and management of PAAs. Corresponding author: Atike Tekeli, M.D. Academic Hospital, Marmara University Foundation, Cardiovascular Surgery, Istanbul, Turkey e-mail: atikemd@gmail.com 114 Marmara Medical Journal 2007;20(2);114-117 Marmara Medical Journal 2007;20(2);114-117 Atike Tekeli, et al Aneurysm of the popliteal artery: case report There was a sufficient pulse over the saphenous vein. After a normal postoperative course, the patient was discharged on postoperative day 7. One month postoperatively, a magnetic resonance angiography of the right lower limb showed a patent saphenous vein graft and his physical examination was normal with palpable popliteal and distal pulses on the postoperative tenth month. both carotid arteries, which were normal. A preoperative coronary angiogram was also normal. Under general anesthesia, the patient was prepared and draped in the supine position. The right greater saphenous vein was harvested beginning at the saphenofemoral juction and ending above the knee. The patient was then put in the prone position and the popliteal artery exploration was performed through a posterior incision. The aneurysm sac was adherent to the adjacent tissues.After systemic heparinization, the popliteal artery was clamped above and below the aneurysm. The aneurysm sac was entered and a huge amount of organized thrombus material was removed (Fig. 2).After this, the greater saphenous vein interposition was performed between the distal and proximal ends of the popliteal artery through an end to end anastomosis (Fig. 3). Fig. 3: Picture showing the saphenous vein graft interposition between the distal and proximal ends of the popliteal artery. DISCUSSION The diagnosis of PAAs is not straightforward because of their nonspecific manifestations. As in our case, the patients usually refer to orthopedic surgeons with vague symptoms such as pain and edema in the lower limb. There may be a pulsatile mass at the popliteal region unless the aneurysm is thrombotic. Otherwise, the diagnosis is challenging and mostly an incidental finding on knee X-rays. It is suggested that nearly one third of the patients with PAA are asymptomatic at the time of diagnosis5. Fig. 1: Digital subtraction angiography showing the popliteal artery aneurysm. The prevalence of PAA is 1% in the general population, it it often bilateral and associated with abdominal aortic aneurysms6,7 The uncertainty over the normal size of the popliteal artery leads to debates in the definition of PAA. In recent studies, the diameter of the normal popliteal artery is measured to be less than 9mm8,9 which was the accepted diameter of the popliteal artery in the textbooks10. Although symptomatic Fig. 2: Organized thrombus material removed from the aneurysm sac. 115 Marmara Medical Journal 2007;20(2);114-117 Atike Tekeli, et al Aneurysm of the popliteal artery: case report also the hospital stay is shorter22. However, this technique has some disadvantages where PAA is concerned and it is reported that stents at the popliteal region are not as effective as for femoral or iliac aneurysms23. Because the popliteal artery is a branching artery and it is located at the knee joint, endografts may kink during knee joint movement and kinking of the grafts may cause important problems17. There are two large series of endovascular treated PAAs to date. In both of these studies, the most widely used stent graft was Haemobahn/Viabahn ( W.L. Gore and Associates, Inc., Flagstaff, AZ, USA). This stent graft is highly flexible and it is appropriate for PAAs24,25. These studies state that the patency rates of open surgery and endovascular treatment of PAAs are similar in selected cases with suitable anatomy. aneurysms of any size should be treated surgically, the management of asymptomatic PAAs is controversial11,12. The accepted threshold for surgical treatment of asymptomatic PAA is considered to be 20mm in diameter5,13. However, it should be kept in mind that the smaller aneurysms also carry the risk of complications14. The symptom profile of PAA ranges from intermittent claudication to rupture of the aneurysm and 50% of asymptomatic PAAs develop symptoms within 2 years after their discovery15,16. It has been reported that surgery has a low mortality rate in asymptomatic patients and prevents ischemic complications that may occur due to thrombosis or distal embolism from the aneurysm17. Thrombus within an aneurysm is an indication for elective surgery whatever the size of the PAA18. Surgical intervention of an asymptomatic PAA has a high limb salvage rate and better outcome than symptomatic aneurysms19. In a study which reviewed 51 cases of PAA, the primary patency rates were 100% at 1 year and 85.6% at 5 years for the limbs undergoing elective repair20. Endovascular treatment was not suitable in our case because the proximal and distal neck of the aneurysm had a length of <1cm which could not offer a secure site of fixation of the stent. As a conclusion, the management of asymptomatic PAAs is still controversial. Elective surgery seems to be the better alternative since it has high graft patency and limb salvage rates. The diagnosis of PAAs should always be kept in mind when a patient refers with a lower limb pain especially in the popliteal region because as stated by Guvendik et al, PAAs are described as being ‘sinister harbingers of sudden catastrophe’26. Medial and posterior approaches are the most preferred incisions for PAA surgery. Medial approach enables the surgeon to harvest the saphenous vein graft from the same incision and allows access to distal arteries. It is suggested that the posterior approach is a simple and safe method and enables aneurysmectomy when PAA is saccular21. We preferred surgical repair in this case through a posterior incision using the saphenous vein as a conduit. The five year patency rate of surgical repair of asymptomatic PAAs is nearly 80% with vein grafts and this leads to increased rates of limb salvage2. REFERENCES 1. 2. Nonsurgical treatment of PAA is another topic open to discussion. Recently, with the advances in endovascular techniques, especially in aortic aneurysms, the peripheral aneurysms also became candidates for this conservative approach. Endovascular approach has some advantages over surgical repair in lower extremity aneurysms as it does not cause high amounts of bleeding, the patients recover in a short period of time and 3. 4. 5. 6. 116 Debasso R, Astrand H, Bjarnegard N, Ryden Ahlgren A, Sandgren T, Lanne T. The popliteal artery, an unusual muscular artery with wall properties similar to the aorta: implications for susceptibility to aneurysm formation? J Vasc Surg. 2004;39:836-842. Galland RB. Popliteal aneurysms: controversies in their management. Am J Surg 2005;190:314-318. Kanko M, Burma O, Ozkan H, Akosman A. Peripheral arterial aneurysms. Turkish J Thorac Carrdiovasc Surg 1997;5:296-299. Pulli R, Dorigo W, Troisi N, et al. Surgical management of popliteal artery aneurysms: which factors affect outcomes? J Vasc Surg 2006;43:481-487. Dawson I, Sie RB, Van Bockel JH. Atherosclerotic popliteal aneurysm. Br J Surg 1997;84:293-299. Dawson I, Sie R, Van Baalen JM, Van Bockel JH. Asymptomatic popliteal aneurysm: elective operation versus conservative follow-up. Br J Surg 1994;81:15041507. Marmara Medical Journal 2007;20(2);114-117 Atike Tekeli, et al Aneurysm of the popliteal artery: case report 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Varga ZA, Locke-Edmunds JC, Baird RN. A multicentre study of popliteal aneurysms. Joint Vascular Research Group. J Vasc Surg 1994;20:171-177. Morris-Stiff G, Haynes M, Ogunbiyi S, et al. Is assessment of popliteal artery diameter in patients undergoing screening for abdominal aortic aneurysms a worthwhile procedure? Eur J Vasc Endovasc Surg 2005;30:71-74. Wolf YG, Kobzatsev Z, Zelmanovich L. Size of normal and aneurysmal popliteal arteries: a duplex ultrasound study. J Vasc Surg 2006;43:488-492. Van Bockel JH, Hamming JF. Lower extremity aneurysms. In: Rutherford RB, editor. Rutherford vascular surgery, 6th ed. Philadelphia: Saunders; 2005: 1534-15351. Schellack J, Smith RB, Purdy GD. Nonoperative management of selected popliteal aneurysms. Arch Surg 1987;122:372-375. Gouny P, Bertrand P, Duedal V, et al. Limb salvage and popliteal aneurysms: advantages of preventive surgery. Eur J Vasc Endovasc Surg 2000;19:496-500. Naylor AR. Regarding “ Small popliteal aneurysms: are they clinically significant?” J Vasc Surg 2003;37:909910. Ascher E, Markevich N, Schutzer RW, Kallakuri S, Jacob T, Hingorani AP. Small popliteal aneurysms: are they clinically significant? J Vasc Surg 2003;37:755760. Michaels JA, Galland RB. Management of asymptomatic popliteal aneurysms: the use of a Markov decision tree to determine the criteria for a conservative approach. Eur J Vasc Surg 1993;7:136-143. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 117 Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-654. Antonello M, Frigatti P, Battocchio P, Sandro L, Cognolato D, Dall’Antonia A, et al. Open repair versus endovascular treatment for asymptomatic popliteal artery aneurysm: results of a prospective randomized study. J Vasc Surg 2005;42:185-93. Galland RB, Magee TR. Popliteal aneurysms: distortion and size related symptoms. Eur J Vasc Surg 2005;30:534-8. Mahmood A, Salaman R, Sintler M, Smith S, Simms MH, Vohra RK. Surgery of popliteal artery aneurysms: a 12-year experience. J Vasc Surg 2003;37:586-93. Aulivola B, Hamdan AD, Hile CN, Sheahan MG, Skillman JJ, Campbell DR, et al. Popliteal artery aneurysms: a comparison of outcomes in elective versus emergent repair. J Vasc Surg 2004;39:1171-7. Beseth BD, Moore WS. The posterior approach for repair of popliteal artery aneurysms. J Vasc Surg 2006;43:940-5. Nagarajan M, Chandrasekar P, Krishnan E, Muralidharan S. Repair of iliac artery aneurysms by endoluminal grafting. Tex Heart Inst J 2000;27:250-2. Henry M, Amor M, Heny I, Klonaris C, Tzvetanov K, Buniet JM, et al. Percutenous endovascular treatment of peripheral aneurysms. J Cardiovasc Surg 2000;41:871-3. Tielliu I, Verhoeven ELG, Zeebregts CJ, Prins TR, Span MM, Van Den Dungen JJ. Endovascular treatment of popliteal artery aneurysms:results of a prospective cohort study. J Vacs Surg 2005;41:561-7. Mohan IV, Bray PJ, Harris JP, May J, MS Stephen, Bray AE, et al. Endovascular popliteal aneurysm repair: are the results comparable to open surgery. Eur J Vasc Endovasc Surg 2006;32:149-54. Guvendik L, Bloor K, Charlesworth D. Popliteal aneurysm: sinister harbinger of sudden catastrophe. Br J Surg 1980;6:294-296. CASE REPORT ECTOPIC URETER DRAINING A POORLY FUNCTIONING RENAL MOIETY CAN BE MISSED BY IVP BUT NOT BY MRU 1 Yusuf Temiz1, Ferruh Şimşek1, Salih Güran2, Rengin Ahıskalı3, Tufan Tarcan1 Marmara University, Urology, Istanbul, Turkey 2 SONOMED, Radiology, Istanbul, Turkey 3 Marmara University, Pathology, İstanbul, Turkey ABSTRACT Ectopic ureter draining a poorly functioning renal moiety can be missed by classical radiological methods such as ultrasonography, voiding cystourethrogram and intravenous pyelogram. In such conditions, use of computerized tomography and magnetic resonance imaging have been advocated to diagnose poorly functioning, abnormal duplex collecting system and ectopic ureter. A case of a 16-year old girl with continuous dribbling incontinence and normal IVP and cystoscopy findings whose ectopic ureter and duplicated system could only be diagnosed by MRU is presented in this case report. Keywords: Ectopic ureter, IVP, MRU, urinary incontinence/physiopathology IVP İLE SAPTANAMAYAN AZ FONKSİYONLU VE EKTOPİK ÜRETERE DRENE OLAN ÜST POL BÖBREĞİN MRU İLE SAPTANMASI ÖZET Kötü fonksiyonlu ve ektopik üretere drene olan böbrek üst polü bazen klasik radyolojik yöntemler olan intravenöz pyelogram, ultrasonografi ve işeme sistoüretrogramı gibi tetkiklerle görüntülenemeyebilir. Bu durumlarda bilgisayarlı tomografi ve magnetik rezonans görüntüleme yöntemleri kötü fonksiyonlu, anormal çift toplayıcı sistemleri ve ektopik üreterleri saptamada kullanılabilir. Bu olguda, devamlı, damlama tarzında inkontinans şikayetiyle başvuran, intravenöz pyelogramı ve sistoskopi bulguları normal olan ancak magnetic rezonans ürografi ile ektopik üreteri ve çift toplayıcı sistemi saptanabilen 16 yaşında kız çocuğunun tanısı ve tedavisi sunuldu. Anahtar Kelimeler: Ektopik üreter, IVP, MRU, idrar inkontinansı/fizyopatoloji al. showed that MRU correctly differentiated between upper and lower poles, demonstrating related parenchyma and collecting system in their patients. In fact, the demonstration of upper pole moiety and ectopic ureteral termination by conventional radiological methods is not always easy. Here, we present a case of a 16-year old girl with continuous dribbling incontinence and normal IVP and cystoscopy findings whose ectopic ureter and duplicated system could only be diagnosed by MRU. CASE REPORT INTRODUCTION Approximately one-half of the girls with ectopic ureter suffer from continuous dribbling incontinence despite a normal voiding pattern 1.Classical radiological methods such as ultrasonography (US), voiding cystourethrogram (VCUG) and intravenous pyelogram (IVP) are usually performed to determine abnormal duplex kidneys and ectopic ureter 2. However, the anatomical assessment may be incomplete if one moiety is markedly dilated or if there is little parenchyma which is poorly functioning 2 . Recently, Magnetic Resonance Urography (MRU) has been used for this aim 2. Fred et A 16-year old girl presented with the complaint of slightly wetting her underwear Corresponding author: Prof. Tufan Tarcan, MD Urology Department,School of Medicine, Marmara University Hospital, Altunizade, Istanbul, Turkey e-mail: tufan@marmara.edu.tr Marmara Medical Journal 2007;20(2);118-121 118 Marmara Medical Journal 2007;20(2);118-121 Yusuf Temiz, et al Ectopic ureter draining a poorly functioning renal moiety can be missed by ivp but not by mru prominent bundles of smooth muscle (Figure 4). There were no immature glomeruli. Cyst formation was not evident. The dysplastic segments were separated by areas of normally developed renal tissue with focal chronic pyelonephritis. Inflammation was present in one dysplastic area adjacent to focal chronic pyelonephritis. Dysplastic segments involved 24 % of renal parenchyma. Findings were compatible with focal solid (non-cystic) renal dysplasia. since early childhood. The physical examination was normal except for a moist genital area. IVP suggested complete ureteral duplication at the left side and a single collecting system at the right side (Figure 1). Voiding cystourethrography revealed a normal urinary bladder and urethra without vesicoureteral reflux. On cystoscopy, a single right ureteral orifice and two left ureteral orifices were visualized. The urodynamic examination was found to be normal. Suspecting an ectopic system which was not yet visible, the patient underwent MRU showing a bilateral ureteral duplication and a right ectopic ureter and opening into the posterior vaginal fornix (Figure 2). Figure 2: Ectopic upper pole kidney (straight arrow) and termination of the ectopic ureter (curve arrow) were shown by MRU. Figure 1: IVP revealed a single collecting system on the right kidney and a duplex collecting system on the left kidney. Thereafter, the patient underwent upper kidney pole nephrectomy (Figure 3) and her continuous incontinence resolved immediately after the operation. In the resected segment, the ureter and the calyces were dilated but corticomedullary differentiation of the kidney was retained. Small nodular masses were presented adjacent to the pelvis. Microscopically, the nodules in the medulla of the kidney were composed of abundant primitive mesenchyme and scanty tubules lined by cuboidal cells. These dysplastic tubules were surrounded by layers of loose and immature connective tissue and Figure 3: Upper pole kidney and ureter (black and white arrows, respectively) are shown after the artery and the veins of the upper pole were ligated. 119 Marmara Medical Journal 2007;20(2);118-121 Yusuf Temiz, et al Ectopic ureter draining a poorly functioning renal moiety can be missed by ivp but not by mru children are exposed to radiation and iodinecontaining contrast medium by CT we believe that MRU is the preferable method for detection of a poorly functioning upper pole moiety. Demonstration of the termination of an ectopic ureter by radiological methods is also not easy. Some ectopic ureters terminate out of the urinary system, such as in the vestibule, vagina and cervix, in 34%, 25%, 5% of cases, respectively 6. Endoscopy of the vagina and urinary bladder are advocated to detect ectopic ureter termination. For example, Plaire et al 8 demonstrated that 58% of ectopic ureters were identified endoscopically in the vagina, vestibule or bladder neck. Figure 4: One of the dysplastic nodules with small collections of tubules surrounded by a myxoid fibrous tissue and smooth muscle. Mild focal lymphocytic infiltration can be seen in the lower left corner only, in the area adjacent to chronic pyelonephritis (arrow). Haematoxylin and eosin x 100 Different possibilities exist for the surgical management of an ectopic ureter of a duplex system. For example, Sen et al. advocated that heminephrectomy should only be performed when the upper pole appears grossly unhealthy at operation 7. In their series, dysplasia was established in only 2 of 19 specimens. In the latter study, upper pole moiety was preserved in combination with ureteropyelostomy in the presence of a good function. DISCUSSION This report presents a case of ectopic ureter of a duplex system opening to the vagina and leading to continuous incontinence that could be demonstrated only by MRU, but not by IVP. Although, 84% of ectopic ureters are diagnosed by IVP during childhood 3, the upper moiety in some cases may not be detected by IVP because of the absence of upper pole calyx or a poorly functioning very thin dysplastic and/or pyelonephritic parenchyma 4. In our case, upper moiety could not be demonstrated by IVP due to a dysplastic and pyelonephritic upper pole parenchyma as revealed in pathological examination. However, MRU with fat sat T2weighted may reveal an ectopic ureter in spite of a dysplastic and pyelonephritic upper pole kidney with little urine secretion (Figure 2). Removing the distal part of the ectopic ureter during heminephrectomy is also debated. Plaire et al. showed that a secondary removal of the ureteral stump was necessary in only 12% of patients who underwent 8 heminephrectomy . However, no patient with urinary incontinence without urinary infection underwent stump removal in their series 8. In our case, the distal part of the ectopic ureter was not removed since the patient did not have any previous urinary tract infection. In conclusion, if an ectopic ureter is suspected in a patient with dribbling incontinence, MRU appears to be the best diagnostic modality because of its low morbidity and high accuracy. It should be kept in mind that IVP can miss a poorly functioning upper pole moiety and its ectopic ureter. Indeed, MRU and computerized tomography (CT) are seen as ideal methods for detecting a suspicious upper pole moiety and ectopic termination of the ureter. For example, Fred et al. showed that IVP and US were significantly inferior to MRU in diagnosing ectopic ureteric insertion results of analyzing children with ectopic ureter (p<0,05)2. In another study, Pantuck et al have proposed the use of CT in order to demonstrate the upper pole moiety and ectopic ureter 5. However, since REFERENCES 1. 120 Fernbach SK, Feinstein KA, Spencer K, Lindstrom CA. Ureteral duplication and its complications. Radio Graphics 1997; 17:109–117. Marmara Medical Journal 2007;20(2);118-121 Yusuf Temiz, et al Ectopic ureter draining a poorly functioning renal moiety can be missed by ivp but not by mru 2. 3. 4. Fred E.A, Nicaise N, Hall M, et al. The role of MR imaging for the assessment of complicated duplex kidneys in children: preliminary report. Pediatr Radiol 2001; 31:215-223. Kaneko K, Ohtsuka Y, Suzuki Y, Yabuta K, Yamataka A, Miyano T. Masked ureteral duplication with ectopic ureter detected by magnetic resonance imaging. Acta Paediatr Jpn 1996;38: 291. Berrocal T, Lo´pez-Pereira P, Arjonilla A, Gutie´rrez J. Anomalies of the distal ureter, bladder, and urethra in children: Embryologic, radiologic, and pathologic features. Radio Graphics 2002;22:1144-1145. 5. 6. 7. 8. 121 Pantuck AJ, Barone JG, Rosenfeld DL, et al. Occult bilateral ectopic vaginal causing urinary incontinence: diagnosis by CT. Abdom Imaging. 1996;21:78-80. Ellerker AG. The extravesical ectopic ureter. Br. J. Surg 1958;45:344. Sen S, Ahmed S. Borghol M. Surgical management of complete ureteric duplication abnormalities. Pediatr Surg Int. 1998;13: 61-64 . Plaire JC, Pope John C. IV, Kropp B P, et al. Management of ectopic ureters: experience with the upper tract approach. J Urol 1997;158:1245-1247. CASE REPORT SEVERE PERIPHERAL NEUROPATHY SECONDARY TO VINCRISTINE THERAPY Ayşe Oytun Bayrak, Hande Türker, Ahmet Yılmaz, Musa Kazım Onar Department of Neurology, School of Medicine,Ondokuzmayıs University, Samsun, Türkiye ABSTRACT Patients with hereditary neuropathy at high risk of severe vincristine neurotoxicity are well known. Here, along with a review of the literature, we described two patients with unrecognized hereditary neuropathy who developed foot drop following low dose vincristine therapy. With this report, we wanted to emphasize the importance of detailed neurologic examination and history taking before initiating therapy. Keywords: Hereditary neuropathy, Vincristin, Neurotoxicity VİNKRİSTİN TEDAVİSİNE BAĞLI GELİŞEN AĞIR PERİFERİK NÖROPATİ ÖZET Herediter nöropatisi olan hastaların vinkristin nörotoksisitesi için yüksek risk taşıdığı bilinmektedir. Burada, daha önceden bilinen nöropatisi olmayan ve düşük doz vinkristin tedavisi sonrası düşük ayak gelişen iki olgu literatür eşliğinde sunulmuştur. Olguların rapor edilmesinin amacı tedavi öncesi ayrıntılı nörolojik muayenenin ve öyküde herediter nöropati varlığının araştırılmasının önemini vurgulamaktır. Anahtar Kelimeler: Herediter nöropati, Vinkristin, Nörotoksisite vincristine treatment. The patient was admitted to our neurophysiology department on the seventh day of his weakness. On neurologic examination the muscle strength of the tibialis anterior and peroneus longus muscles were 0/5 on the left and the muscle strength of the other lower extremity muscles were 4/5 bilaterally. Deep tendon reflexes were decreased at the upper and absent at the lower limbs. He had atrophy in the tibialis anterior muscles bilaterally. Figure 1 shows atrophy in the tibialis anterior muscles and foot drop on the left side (Figure 1). INTRODUCTION The vinca alkoloid vincristine is a commonly used chemotherapeutic agent in the treatment of different types of malignancies. Its usage can be limited because of the peripheral neurotoxicity which is related to dosage, frequency of administration and patient age 1. Patients with hereditary neuropathies are at risk for severe neurotoxic reactions 2,3. Several patients with hereditary neuropathy in whom severe vincristine toxicity developed during their treatment have been reported in the literature 3-8. Here, along with the review of the literature, we described two patients with unrecognized hereditary neuropathy who developed severe sensorimotor neuropathy following vincristine treatment. CASE REPORT Case 1 A 12-year-old boy diagnosed as hepatic tumor, developed rapid foot drop on the left side following 1.5 mg/m2/wk intravenous (iv) Electrophysiological examination included nerve conduction studies (NCs) and needle electromyography. Ulnar, peroneal and posterior tibial motor NCs including F-waves were performed. Sensory NCs included ulnar nerve on the left side and sural nerve bilaterally. The amplitudes of ulnar and posterior tibial compound muscle action potentials (CMAP) were moderately reduced. Corresponding author: Ayşe Oytun Bayrak, MD Ondokuzmayıs Üniversitesi, Nöroloji, Samsun, Türkiye e-mail: oytun.bayrak@gmail.com Marmara Medical Journal 2007;20(2);122-126 122 Marmara Medical Journal 2007;20(2);122-126 Ayşe Oytun Bayrak, et al Severe peripheral neuropathy secondary to vincristine therapy The distal latencies and conduction velocities of the ulnar nerve were normal. The distal latency of the posterior tibial CMAP was normal on the left while moderately prolonged on the right side. The CMAPs of peroneal nerves could not be obtained and peroneal F-waves were absent bilaterally. The amplitude and conduction velocity of the ulnar sensory nerve action potentials (SNAPs) were moderately reduced while sural nerve SNAPs could not be obtained. Nerve conduction studies revealed severe axonal degeneration in the lower extremities, more pronounced on the left, while there was a moderate degree of axonal degeneration in the upper limbs. Needle electromyography showed severe chronic denervation with reduced recruitment of polyphasic, large amplitude, and long duration motor unit potentials. The tibialis anterior muscle showed fibrillation potentials and positive sharp waves at rest and no voluntary activation on the left side. Table I summarizes the results of the electrophysiological studies of the patient (Table I). The amplitudes of ulnar CMAPs were moderately reduced and the distal latencies were moderately prolonged. The amplitudes of posterior tibial CMAPs were severely reduced and the distal latencies were prolonged. The CMAPs of the peroneal nerves could not be obtained bilaterally. Fwaves of the peroneal and posterior tibial nerves were absent. The latencies of the ulnar and sural SNAPs were moderately prolonged. These electrophysiological findings revealed severe axonal sensory-motor polyneuropathy. Table II summarizes the results of the electrophysiological studies of the patient (Table II). Case 2 A 15-year-old boy was diagnosed as having acute myeloid leukemia and received induction chemotherapy consisting of vincristine, cytosine arabinoside and mitoxantron. He developed bilateral foot drop following three 1.5 mg/m2/wk iv doses of vincristin treatment. He was admitted to our neurophysiology department on the sixth day of his complaints. On neurologic examination, the muscle strength of the tibialis anterior and peroneus longus muscles were 1/5, the tibialis posterior muscle was 2/5 bilaterally. The strength of the other muscles was normal. Deep tendon reflexes were absent. Besides glove-stocking type hypoesthesia, he had hammer toe and pes cavus deformities bilaterally (Figure 2). Figure I: Figure 1shows atrophy in the tibialis anterior muscles and foot drop on the left side. Electrophysiological examination included only NCs. Needle electromyography could not be performed because of low platelet levels. Ulnar, peroneal and posterior tibial motor NCs including F-waves were performed. Sensory NCs included ulnar nerve on the left side and sural nerve bilaterally. Figure II: Figure 2 shows the hammer toe and pes cavus deformity of the patient. 123 Marmara Medical Journal 2007;20(2);122-126 Ayşe Oytun Bayrak, et al Severe peripheral neuropathy secondary to vincristine therapy The severe neurologic involvement following low doses of vincristine and the findings after neurologic examination of both cases indicated an underlying chronic process like a hereditary neuropathy. Table I: Results of the nerve conduction study of the first patient Side Nerve Record Late ing ncy N N Ampli tude (mv- (Mv- µV) µV) N F Distanc NC e V min (m/s . ) late (cm) N ncy Left Ulnar ADM 3.0 <3.3 6 >6.0 180 60 >36 wrist elbow 6.0 <7.2 6 above 6.7 <9.1 6 Not obtain 70 22. <29 9 .6 90 elbow Left Peroneal EDB ankle Righ Peroneal t Left EDB ed Not ankle Post.tibi AHL al ankle poplite - - obtain ed 5.0 <5.0 2 >6 300 40 >40 43 <53 .5 12.7 2 a Righ Post.tibi AHL t al ankle poplite 5.4 <5.0 2 >6 300 44 >40 Ulnar Sensor 5th y 12.2 1.5 3.3 <3.6 Not obtain 15 >21 120 36 >39 finger Left Sural Sensor y Righ t Sural Sensor y <53 .5 a Left 43 ed Not obtain ed Footnotes: Abbreviations for both tables NCV: Nerve conduction velocity EDB: Extensor digitorum brevis ADM: Abductor digiti minimi Min. latency: Minimal latency N: Normal value (According to our lab. normals in the same age group) mv: milivolt *Pathologic values are written in bold 124 AHL: Adductor hallucis longus cap.fib: Capitulum fibulae Marmara Medical Journal 2007;20(2);122-126 Ayşe Oytun Bayrak, et al Severe peripheral neuropathy secondary to vincristine therapy TableII:Results of the nerve conduction study of the second patient Side Left Nerve Ulnar Recordin Laten g cy ADM 3.9 N N Amplit Distance (cm) ude <3.3 NCV N (m/s) F min. (mv- (Mv- laten µV) µV) cy 3 >6.0 230 47 N >36 31.8 wrist <29. 6 elbow 8.9 <7.2 3 above 9.8 <9.1 3 Not obtained Not obtained 8.5 <5.0 90 94 380 33 elbow Left Peroneal EDB Right Peroneal EDB Left Post.tibial AHL ankle ankle 0.3 >6 >40 - ankle Right Post.tibial 5 poplitea 20.3 AHL 9.0 0.3 <5.0 0.2 >6 380 32 >40 ankle Left Ulnar <53. - <53. 5 poplitea 21.0 Sensory 3.6 0.2 <3.6 27 >21 120 33 >36 5th finger Left Sural Sensory 5.4 <4.0 11 >9 140 25 >32 Right Sural Sensory 5.3 <4.0 9 >9 140 26 >32 literature and these cases suggested that there may be an increased sensitivity to low doses of vincristine in patients who have a preexisting inherited polyneuropathy4. Two similar cases with hereditary polyneuropathy have been described where a severe neuropathy developed after receiving 6 mg vincristine. The diagnosis of hereditary neuropathy in one of the cases was prompted by the observation of an abnormal foot shape and so the authors recommended a careful examination including inspection of hands and feet to exclude hereditary neuropathy before initiating vincristine treatment5. Graf et al reported three patients with hereditary neuropathy who had at least one family member with 17p11.1-12 duplication and developed severe neuropathy after receiving initial doses of vincristine. They recommended taking a detailed family history before vincristine treatment in such cases6. Similar experiences have been described in a DISCUSSION Vincristine neurotoxicity is well known and characterized with a mixed distal sensorymotor polyneuropathy. Toxicity is related to the dosage, frequency of administration and patient age1. Significant neurotoxicity is not generally seen with cumulative dosage, although severe neurotoxicity has been reported after small dosages of vincristine in patients with subclinical neurological diseases3-8. McGuire et al. reported a patient with unrecognized hereditary neuropathy who developed a severe sensorimotor polyneuropathy following 3.5 mg of vincristine treatment. They noted global weakness, decreased tendon reflexes and atrophy of the anterior compartment muscles and prominent foot arches. The patient had a family history of hereditary neuropathy. They also reviewed six similiar cases from the 125 Marmara Medical Journal 2007;20(2);122-126 Ayşe Oytun Bayrak, et al Severe peripheral neuropathy secondary to vincristine therapy patient with Ewing’s sarcoma who developed severe weakness of upper and lower extremities7 and in a patient who developed areflexia, lower extremity weakness and an increase in cavus deformity8. Schiavetti et al described a patient with Wilms tumor who was previously asymptomatic and had no family history for hereditary neuropathies. Neurologic examination revealed global weakness, decreased tendon reflexes and distal wasting of the legs and high arches. The patient developed severe but reversible neuropathy after vincristine treatment and genetic studies suggested a diagnosis of hereditary neuropathy3. Most of these cases reported in the literature concerned pediatric or teenage patients. The common clinical findings were muscular weakness, atrophy, decreased or absent tendon reflexes and foot deformities, as in our cases. Patients with hereditary neuropathy are at high risk of severe vincristine neurotoxicity and this makes the exclusion of diagnosis of hereditary neuropathy a necessity before initiating therapy. The studies including nerve biopsies and electrophysiological examinations demonstrate that vincristine causes primary axonal degeneration by binding and inactivating tubulin9. This effect was found consistent with disruption of the fast component of axonal transport10. On the other hand, slow axonal transport was abnormal in most of the hereditary neuropathies, therefore severe vincristin toxicity in patients with hereditary neuropathies was thought to be related with the impairment of both slow and fast axonal transport4. Our cases had no family history or known neurological diseases. One of our cases had atrophy in the tibialis anterior muscles bilaterally while the other had hammer toe and pes cavus deformities bilaterally. The severe neurologic involvement following low doses of vincristine and the findings of neurologic examinations of both of the cases suggested an underlying chronic process like a hereditary neuropathy, although genetic examination could not be performed. We recommend a careful neurologic examination to exclude an underlying hereditary neuropathy and taking a detailed family history before initiating vincristine in order to protect the patients from the severe neurotoxic effects of vincristine therapy. REFERENCES 1. Legha SS. Vincristine neurotoxicity. Medical toxicology. 1986; 1: 421-427. 2. Chauvenet AR, Shashi V, Selsky C, Morgan E, Kurtzberg J, Bell B. Vincristine induced neuropathy as the initial presentation of Charcot Marie Tooth disease in acute lymphoblastic leukemia. A Pediatric Oncology Group Study. J Pediatr Heamatol Oncol 2003; 25:316320. 3. Schiavetti A, Frascarelli M, Uncini S, Novelli A. Vincristine neuropathy: Neurophysiological and Genetic Studies in a case of Wilms Tumor. Pediatr Blood Cancer. 2004; 43: 606-609. 4. McGuire S, Gospe S, Dahl G. Acute vincristine neurotoxicity in the presence of motor and sensory neuropathy type 1. Med Pediatr Oncol 1989; 17: 520523. 5. Igarashi M, Thompson E, Rivera G. Vincristine neuropathy in type I and type II Charcot Marie Tooth Disease. Med Pediatr Oncol 1995; 25:113-116. 6. Graf WD, Chance PF, Lensch MW, Eng LJ. Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot Marie Tooth disease type 1A. Cancer. 1996; 7:1356-1362. 7. Neumann Y, Toren A, Rechavi G, Seifried B, Shoham NG, Mandel M. Vincristine treatment triggering the expression of asymptomatic Charcot Marie Tooth disease. Med Pediatr Oncol 1996; 26:280-283. 8. Orejana-Garcia AM, Pascual-Huerta J, Perez-Melero A. Charcot-Marie-Tooth disease and vincristine. J Am Podiatr Med Assoc 2003; 93:229-233. 9. Sahenk Z, Brady ST, Mendell JR. Studies on the pathogenesis of vincristine induced neuropathy. Muscle Nerve 1987; 10: 80-84. 10. Allen RD, Metuzals J, Tasaki I, Brady ST, Gilbert SP. Fast axonal transport in squid giant axon. Science 1982; 218:1127-1129. 126 REVIEWS MITOCHONDRIAL DNA AND CANCER Cenk Aral, Ayşe Özer MÜ Tıp Fakültesi, Tibbi Biyoloji, İstanbul, Türkiye ABSTRACT Mitochondrial DNA has been proposed to be involved in carcinogenesis because of high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. In this paper, we review mitochondrial genome instability, relation of mitochondrial DNA mutations with apoptosis and mitochondrial genomic aberrations reported in solid tumors of the thyroid, colorectal, breast, and gastric cancers. Keywords: Mitochondrial DNA, Genomic instability, Apoptosis, Mutation, Solid tumors MİTOKONDRİYAL DNA VE KANSER ÖZET Mitokondriyal DNA' nın, nükleer DNA' ya kıyasla mutasyonlara daha duyarlı olması ve tamir mekanizmalarının sınırlılığı nedeniyle karsinogenezde rol aldığı öne sürülmüştür. Bu derlemede tiroid, kolorektal, meme ve gastrik kanserlerde, mitokondriyal genom kararsızlığı, mitokondriyal DNA mutasyonlarının apoptozis ile ilişkisi ve mitokondriyal genomdaki değişimler değerlendirilmiştir. Anahtar Kelimeler: Mitokondriyal DNA, Genomik kararsızlık, Apoptozis, Mutasyon, Solid tümörler The abbreviations used are: 8-oxodG, 8oxodeoxyguanine; AIF, apoptosis-inducing factor; ATP, adenosine-3-phosphate; CD, common deletion; CRC, colorectal carcinoma; DAP3, death associated protein 3; DL, ductal lavage; D-loop, displacement loop; FA, follicular adenoma; FNA, fine needle aspirate; LOH, loss of heterozygosity; MMR, mismatch repair; MSI, microsatellite instability; MSNT, matched surrounding normal tissue; mt, mitochondrial; mtDNA, mitochondrial DNA; mtGI, mitochondrial genome instability; mtMSI, mitochondrial microsatellite instability; nDNA, nuclear DNA; NGI, nuclear genome instability; OXPHOS, oxidative phosphorylation system; POL γ, DNA polymerase γ; PTC, papillary thyroid carcinoma; RFLP, restriction fragments lenght polymorphism; ROS, reactive oxygen species; SSM, slipped-strand mispairing; TFAM, mitochondrial transcription factor A; TRAIL, TNF-related apoptosis-inducing ligand. INTRODUCTION Malignant cell transformation is a multistep process that usually involves a cascade of events in which the sequential malfunction of oncogenes, tumor suppressors, mismatch repair (MMR) genes and telomere replication regulators generate changes in the cell cycle. Recently, alterations of mitochondrial DNA (mtDNA), which were not found in normal tissues from the same individual, have been reported in many tumors. In this review, we will focus on the current knowledge on the role of these alterations in the carcinogenesis of human tissues. 1. Mitochondrial genome Human cells have hundreds of mitochondria which are semi-autonomously functioning organelles producing cellular ATP as power plants of the cell. Each cell contains varying numbers of mitochondria depending on energetic requirements. The human oocyte is estimated to contain 100,000 mitochondria, while spermatozoa have relatively few. Each Corresponding author: Prof. Dr. Ayşe Özer MÜ Tıp Fakültesi, Tibbi Biyoloji, İstanbul, Türkiye mail: aozer@marmara.edu.tr Marmara Medical Journal 2007;20(2);127-136 127 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer mitochondrium contains a number of copies of its own genome (10 to more than 1000) whose complete sequence was reported in 19811,2. Human mitochondrial DNA is a double stranded, supercoiled, circular molecule, which consists of 16,568 base pairs. The compact mtDNA molecule encodes 37 genes; 13 of them encode polypeptides of the oxidative phophorylation system (OXPHOS), 22 tRNAs and two types of rRNAs. The OXPHOS consists of five large enzymatic complexes and is formed from the gene products of 74 nuclear genes and 13 mitochondrial genes (Fig 1) (Table I). The two complementary strands of mtDNA, based on their guanine (G) content, are named as heavy and light strands (H-strand and Lstrand, respectively). Guanine-rich H-strand of mtDNA encodes 28 of the 37 genes while L-strand encodes the remaining genes2,3. A non-coding control region extending from 16,024 to 576 nucleotide positions contains three conserved sequence blocks and a displacement loop (D-loop). Moreover, promoters and enhancers for mitochondrial transcription, as well as the origin of replication for H-strand, reside in this region. Figure 1: Human mitochondrial DNA3. 128 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer Mitochondria are the major intracellular producers of reactive oxygen species (ROS) as a side-product of OXPHOS. Deficiency in the OXPHOS reduces energy supply and enhances ROS production that may induce mutation and oxidative damage to mtDNA. This increase in the ROS concentration of mitochondrial microenvironment gives rise to a rate of mitochondrial genome mutations 10 to 100 fold higher than the nuclear DNA (nDNA) mutation rate. Moreover, in contrast to nDNA, mtDNA does not contain protective histon proteins and intronic sequences. However, it has been reported that mitochondrial transcription factor A (TFAM) is bound to mtDNA and forms histone-like structures4,5. In addition, mtDNA repair is poor and the replication process is error prone when compared to nDNA. Given the high copy number of mtDNA per cell, mutated mtDNA can be found together with wild-type mtDNA. This phenomenon is called as heteroplasmy. At the homoplasmic state, there is a single type of mtDNA existing in a cell. Clinical expression of a given mtDNA mutation mainly depends on the proportion of mutated and wild-type mtDNAs at the heteroplasmic state. Depending on the energetic demands of a particular cell, the level of mutated genomes is required to produce a phenotypic expression (threshold effect)6. 1.1. Reactive oxygen species (ROS) and mtDNA As noted above, mitochondria are the main targets for ROS, which are produced by themselves. Oxidative damage to DNA results in the base or sugar adducts, single and double strand breaks, as well as cross-links to other molecules. Many of these mtDNA modifications are mutagenic, and thought to contribute to cancer, aging and neurodegenerative diseases7. More than 20 base lesions have been identified as a result of hydroxyl radical attack. Thymine glycol, the most common pyrimidine lesion, has been determined to block replication and transcription rather than to cause mutagenesis8. Generally, hydroxyl radicals produce purine modifications. The most common and extensively studied purine modification is 8-oxodeoxyguanine (8oxodG) and it has been found to cause GC → TA transversions9. The mtDNA polymerase γ (POL γ) also introduces this signature mutation at high frequency when replication pasts 8-oxodG10. Since increased formation of ROS-related DNA modifications has been reported in various studies with human cancers, it is not clear whether overproduction of ROS is a result or consequence of neoplastic transformation11. On the other hand, the effect of ROS on mitochondria may result in deficiency in the apoptotic behaviour of cells and mitochondrial genome instability (mtGI) as well as nuclear genome instability (NGI), which are the main molecular events frequently observed in malignant cells11, as will be discussed below. Mitochondrial DNA undergoes fragmentation and degradation in the mt-environment or in the cytoplasm followed by severe damage. In some cases, transposition of mtDNA fragments within the nuclear genome is detected, which may be responsible for malign transformation in certain cases of cell transformation12. 1.2. Mitochondrial genome instability High rates of spontaneous mutations, epigenetic factors such as abnormal methylation and loss of heterozygosity (LOH) in MMR gene/s explain nuclear genome instability in several types of hereditary and sporadic human tumors. So far, different rates and types of mitochondrial genome instability have been analyzed in almost all human tumors, but the information is still insufficient to explain the role of the mtGI in the origin and evolution of human cancers. Since DNA damage, slipped-strand mispairing (SSM) and defective DNA repair generate the genomic changes detected for the nDNA of tumors, it has been suggested that these three mechanisms are also involved in the formation of mtDNA mutations. Mitochondrial DNA contains several monoand dinucleotide repeats. (CA)n microsatellite starts from 514 bp position of the D-loop and it shows different alleles varying in size by one repeat in human populations. 129 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer Table I: Number of mitochondrial and nuclear DNA-encoded gene products of electron respiratory chain67. Protein mtDNA gene product mtDNA complex gene nDNA product (N) product (N) I ND1, ND2, ND3, ND4, ND4L, ND5, ND6 7 36 II - 0 4 III Cytochrome b 1 10 IV Cytochrome c oxidase I, II and III 3 10 V ATPase 6 and 8 2 14 13 74 Total gene deletions. During this SSM, the intervening segment forms single strand loops and becomes thereafter deleted, including in the deletion of one of the repeats20-24. Accordingly, this is the mechanism for the 4997 bp deletion in breast cancer20 and the 50 bp deletion in gastric carcinomas25. Homopolymeric C tract extends from 16,184 to 16,193 bp of the D-loop, which is interrupted by a T at 16,189 bp position. It has been proposed that the enhanced sensitivity to ROS and lipid peroxides due to the triple stranded DNA structure and attachment to the mt-membrane of the D-loop region may explain the increased rate of the D-loop point mutation in breast cancer13. It is very well known that defective DNA repair is always a component of the mechanisms leading to DNA changes. A homozygous defective function of one or more MMR genes plays an important role in malignant transformation. Since MMR gene defect shows a marked positive correlation with high-frequency of microsatellite instability (MSI)26,27, there is no correlation between mtMSI and mtGI in colorectal17,18 and mammary cancers13. These results indicate that NGI and mtGI in these tumors respond to different mechanisms of defective repair. The first step leading to allelic changes in homopolymeric tracts and microsatellites is the misalignment of repeats in complementary DNA strands with the formation of single strand loops of one or more bases14,15. SSM is an intra-helical event involving the misalignment of repeats in complementary DNA strands. The mechanism producing the allelic changes in breast cancer (CA)n microsatellite can be explained by SSM13. The chance of alignment shifting is higher for homopolymeric or dinucleotide repeats than for repeats of three or more base pairs and higher for continuous homopolymers than for homopolymers interrupted by a base different from the repeated one16. Moreover, the cause of the homopolymeric tract instabilities have been detected in colorectal, gastric and breast cancers13,17-19. POL γ is encoded by nuclear genes as all other proteins required for mt-genome replication28. It is responsible for mtDNA replication and error prone due to a ineffective proofreading efficiency29,30. Thus, probably most forms of mt-genome mutations are explained by increased DNA damage plus normal POL γ DNA synthesis. It has been proposed that the rate of mtDNA mutations is increased when POL γ is defected due to The pairing between two direct repeats separated by an intervening DNA fragment is one of the mechanisms producing mt130 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer On the other hand, Schoeler et al.,38 reported a relatively higher sensitivity to TRAIL induced apoptotic stimuli at cybrid cells with low levels of mtDNA 4977 bp common deletion (CD). Controversial results obtained by various laboratories may be due to experimental differences such as cell lines used and types of apoptotic induction. Since a lot of studies revealed these findings, molecular mechanisms underlying the effect of mtDNA mutations on apoptosis are still a mystery. It has been found that the mtDNA mutations induce protective expression of Bcl-2 and Bfl-1, prosurvival proteins in cardiac myocytes39. Park et al.,40 reported an increase in the expression of antioxidant enzymes at mitochondria depleted cells. They suggested that this adaptive response in the gene expression renders cancer or aged cells with aberrant mtDNA mutations, resists against oxidative stress, hosts anti-cancer surveillance against chemotherapeutic agents, conferring survival advantage. Jacques et al.,41 showed that expression of DAP3 (Death associated protein 3) is strongly dependent on mtDNA maintenance. DAP3 is a component of the mitochondrial ribosome small subunit and a major positive mediator of apoptosis. According to their data, DAP3 was not expressed at mtDNA-less cells, which exhibited a relative resistance to apoptosis induced with drugs such as strausporin. In the mtDNA-less cells 12S and 16S rRNAs expression is low and this may result in a failure to assembly mitochondrial ribosomes. The authors concluded that mutations of mtDNA, resulting in lower rRNA expression, might be responsible for apoptotic resistance in diseased cells. 2. Mitochondrial DNA mutations and cancer 2.1. Thyroid cancer Using two-dimensional gene scanning technique, Yeh et al.,42 examined 21 cases of thyroid tumors [1 Hurtle cell carcinoma, 4 follicular adenomas (FA), 13 papillary thyroid carcinomas (PTC), 1 follicular carcinoma, 1 insular carcinoma and 1 medullary carcinoma], 6 cases with non-neoplastic thyroid pathology, 30 control tissues, 9 foetal mutations, epigenetic factors or inhibition by certain antiviral drugs31-33. Zeviani et al.34 proposed that mitochondrial topoisomerases I and II genes are additional causes of mtGI in tumors. 1.3. Mitochondrial DNA mutations and apoptosis Mitochondria play an important role in the apoptotic processes. At the intrinsic pathway of apoptosis (e.g. apoptosis due to internal signals such as DNA damage), the first step is the induction of pro-apoptotic (BAX, BID, BAD, NOXA, PUMA) and the downregulation of antiapoptotic (Bcl-2, Bcl-xL, Bfl-1) Bcl family proteins. The second step is the formation of pores in the mitochondrial membrane and release of several mitochondrial proteins such as cytochrome c, SMAC/Diablo and apoptosis-inducing factor (AIF) to cytoplasm. These factors then form large apoptosome complexes, which lead to caspase activation and then apoptosis.The contribution of mtDNA mutations to the apoptotic behaviour of cells is a great interest of research. Recently, Lee et al.35 have reported that the resistance against apoptosis, when induced by TRAIL (TNF-related apoptosis-inducing ligand), was increased in the cells with diminished mitochondrial function Thus, it has been suggested that mutations in mitochondrial genes might serve as a selection advantage over normal cells with intact mitochondrial function. In contrast, Liu et al.36 have reported that mutation or depletion of mtDNA increased the susceptibility of the cell to apoptosis, induced with strausporin. Moreover, Shidara et al.,37 investigated the contribution of mtDNA mutations in tumor development and progression. In this study, cybrids containing a single nucleotide mutation at mitochondrial ATPase6 gene were inoculated to nude mice, which demonstrated higher rates of tumor development and progression, compared to wild-type mice. Furthermore, they reported a lower frequency of apoptotis at cybrids both in vivo and in vitro and concluded that mutations at the mitochondrial genome offer an advantage to cells for promoting tumorigenesis, especially at the early stages. 131 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer thyroid tissue and 9 non-thyroid tissues for mtDNA mutation. They identified 3 somatic missense mutations in 23% of the papillary thyroid cancer cases. These three mutations were found in tRNAasp, ND3 and CYT B genes. Moreover, sequence variations in both neoplastic and non-neoplastic thyroid tissues were identified, and the authors concluded that these non-somatic variations may be related to tumour progression in the thyroid. cancer patients from Belarus after the Chernobyl accident and 40 sporadic thyroid cancer patients from Germany showed that alterations of D310 region are related to the age of patients at the time of surgery, but not to the degree of radioactive contamination46. Recently, Maximo et al.,47 examined sequence alterations in three repetitive regions (D310, D514, D568) in malignant and benign thyroid tumors. They found that these alterations were common in both malignant and benign tumors and cannot be considered as a marker of malignancy. Maximo et al.,43 investigated the existence of 4977 bp common deletion in 79 benign and malignant thyroid tumors (Hurtle and nonHurtle cell neoplasms). They found mtDNA CD in all of the Hurtle cell tumors (100%), in 33.3% of adenomas and 18.8% of papillary carcinomas without Hurtle cell features. The authors also found 57 somatic mutations, mostly transitions, in coding genes including tRNA genes of tumor samples. Follicular and papillary carcinomas displayed a significantly higher prevalance of mutations of complex I genes than follicular adenomas. On the other hand, the prevalance of OXPHOS mutations in Hurtle cell tumors did not statistically differ from non-Hurtle cell tumors. In an ongoing research performed in our laboratory, we are examining D310 alterations using restriction fragments length polymorphism (RFLP) assay in thyroid cancer patients. In this way, enzymatic digestion of PCR products of D310 by using BsaXI, it is possible to distinguish 7-C carriers at the first stretch. Thus BsaXI positive case is identified as 7-C carrier whereas BsaXI negative case contains more or less than 7-C in this region. According to our preliminary data, 16 of 37 thyroid cancer patients were BsaXI positive (eg. 7-C at D310 region) and 20 of 37 patients were BsaXI negative. Only one patient showed heteroplasmy and there was no difference between tumoral and non-tumoral tissues. Rogounovitch et al.,44 investigated mutations in mtDNA samples of PTC and FA patients from regions contaminated with radioisotopes after the Chernobyl accident. Common deletion (4977 bp) was quite prevalent in PTC and FA, therefore it was unlikely to be representative of thyroid tumors. The authors also reported that large scale deletions other than CD were higher in radiation associated tumors as well as CD when compared to the non-radiation associated group (spontaneous PTC or FA). 2.2 Colorectal Cancer Aikhionbare et al.,48 examined the relationship between mtDNA alterations and colorectal carcinogenesis in 25 adenomas, 27 colorectal carcinomas (CRC) and their matched surrounding normal tissues (MSNT). A total of 38 nucleotide variants were identified; however, none of them appeared to be a marker for a particular adenoma of CRC. Moreover, the numbers of these variants were less in precancerous tissues than in CRC. They suggested that this may be a useful approach for distinguishing the progressive stages of colorectal adenomas. Sequence alterations in the D-loop region of mtDNA were also investigated in thyroid cancer, as well as other types of human cancers. Tong et al.,45 investigated D310 polymorphisms of the D-loop region. This region consists of two cytosine stretches interrupted by a thymidine nucleotide (C7TC5). Alterations of the cytosine number at the first stretch were found in 5.7% PTC, 5.6% medullary carcinomas, 11.1% anaplastic carcinomas and 11.1% follicular thyroid carcinomas. Another study including thyroid Nishikawa et al.,49 found a higher mtDNA mutation rate in the colonic tissues of patients with ulcerative colitis than in those of inflammatory disease-free patients. They suggested that accumulation of mtDNA 132 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer mutations, as well as nDNA mutations after inflammation, may be an indicator of carcinogenesis. On the other hand, the authors reported the existence of homoplasmic mutations in both inflammatory and noninflammatory regions of the colonic mucosa. Greaves et al.,50 showed that a mitochondrial mutation in a single cryptic cell could be dominated in a patch of cryptic tissue of the colon by clonal expansion by cryptic fission. 24% were heteroplasmic (BsaXI +/-). No significant differences were found between CRCs and MSNTs. When we compared the BsaXI status of CRC patients with that of the healthy controls, a significant difference was found. 2.3. Breast cancer The D-loop region of 40 breast cancer samples and their MSNT were analyzed using RFLP analysis13. It was found that 47.5% of the cases were mutated in MnlI restriction sites representing a 216-fold increase over the spontaneous rate in the female germline. Lee et al.,51 analyzed the D-loop region of mtDNA in a variety of human tumors including CRC and found sequence alterations in 40% of the patients, mostly in the D310 region (90%). They also reported a significant decrease in the mtDNA copy number in 28% of the cases when compared to MSNT, especially in the later stages of CRC (stage III and IV). The authors suggested that D-loop mutations were important markers of carcinogenesis, but the molecular mechanism by which the mtDNA copy number is decreased by cancerassociated D-loop mutations is not clear. However, in another study, D-loop alterations were found in only 8% of colorectal cancers without a significant relation between the stage of the disease and the occurrence of mutation52. In another study that involved entire mtDNA mutation scanning by temporal temparature gel electrophoresis (TTGE), 74% of the cases (14/19) were found to be mutated55.The percentages of these mutations were 3.7%, 14.8% and 81.5% in rRNA genes, protein encoding genes and D-loop region, respectively. The D310 region in the D-loop region of mtDNA was also examined by various researchers in breast cancer patients. Parrella et al.,56 analyzed D310 mononucleotide repeat changes in 64 breast tumors and found D310 alterations in 12 cases (19%). The majority of these alterations were 1 or 2 bp insersions or deletions of the first stretch of cytosines, except the two cases that showed either an 8 bp or a 9 bp deletion. The same deletion or insersions were also found in the corresponding fine needle aspirate (FNA) specimens when available. The entire mitochondrial genome was sequenced in 18 primary breast tumors and 7 mutations were detected in the coding (ND1, ND4, ND5 and cytochrome b genes) and non-coding D-loop region. Similarly, several studies revealed the possibility of the examination of D310 alterations in ductal lavage (DL) and FNA specimens57,58. Lievre et al.,53 analyzed entire mitochondrial genome in 11 CRC patients and found 10 somatic mutations in seven patients. Most of the nucleotide changes (80%) were found in the D-loop region, while the remaining were in the coding regions (cytochrome c oxidase 1 and 3). The authors further analyzed D-loop region (nt 190-590) in 365 CRC patients and found 142 D-loop alterations. Most of these alterations (132) were found in the D310 region. They also reported that 3-year survival rate and the efficacy of adjuvant chemotherapy were significantly lower in patients with D-loop mutations. Zhu et al.,59 scanned mtDNA for large deletions in breast cancer tissues, their MSNT and in normal breast tissues from women without breast cancer. Common deletion of mtDNA had similar frequency in both cancerous and in normal tissues, whereas novel 3,938 bp and 4,388 bp deletions were Recently, using PCR-based restriction fragments length polymorphism assay with BsaXI restriction enzyme, we analyzed the D310 region in the CRC and MSNT samples, as well as in the samples from healthy individuals54. Thirty-six percent of the studied samples were homoplasmic BsaXI (+) and 133 Marmara Medical Journal 2007;20(2);127-136 Cenk Aral, et al Mitochondrial DNA and cancer more frequent in the cancerous tissue than observed in MSNT. Therefore, it was suggested that these novel deletions may be a marker for breast malignancy. Consistent with these data, Dani et al.,60 also noticed a lower frequency of CD in tumoral tissues including breast cancer. significantly decreased mtDNA copy number (below 90%) when compared to MSNT. By contrast, 22.6% of the samples had significantly higher mtDNA copy numbers (above 110%). In contrast to colorectal carcinomas indicated above, decrease or increase of mtDNA copy number appeared to be independent of the stage of the disease. In our recent study54, we examined 25 breast cancer specimens for D310 polymorphism with RFLP. BsaXI negative cases had lower frequency in the breast cancer samples (11/25, 44%) when compared to the control group (27/41, 65.9%), but this difference was not statistically significant. Eigtheen D-loop mutations were reported by Zhao et al.,64 in 20 gastric cancer patients. In this study, the level of ROS, rate of cell apoptosis and proliferation were found to be higher in patients with mutations than those in controls. It was concluded that D-loop mutations were important in the development and progression of gastric cancer through the effect of increased ROS. 2.4. Gastric cancer Tamura et al.,61 screened control region of mtDNA in 45 Japanese gastric carcinoma patients with PCR-single stranded conformation polymorphism assay (SSCP) and found only two heteroplasmic mutations in nucleotide positions 248 and 16,129. In a different study, Maximo et al.,62 found a high percentage of CD in gastric cancer (53.1%) patients and suggested that gastric cancer is more prone to have gross genetic alterations of mtDNA than to exhibit signs of fine genetic instability. Wu et al.,65 examined D-loop mutations and the presence of CD in 31 gastric cancer samples. In this study, 10 of the patients showed sequence alterations in the D310 region and a total of 17 mutations were reported, including a case with 3 mutations. Approximately half of the mutations were reported as homoplasmic. On the other hand, CD was found in 10% of the cancerous tissues of the patients, whereas it was found in 55% of the MSNT. It was also shown that 55% of the patients had significantly decreased mtDNA copy number, which was not associated with D-loop mutations. The D-loop and downstream genes 12s rRNA-tRNAphe were studied for sequence variations in 22 gastric cancer samples and their MSNT by direct sequencing. In this study, PolyC and (CA)n instabilities were demonstrated in the D-loop including the D310 region without a significant difference between cancerous tissue versus MNST63. Moreover, sequence variations in 12s rRNAtRNAphe genes and a significant correlation between the frequency of these variations and the differentiation degree of gastric carcinoma were detected. Recently, D310 alterations were found in 14 of 94 gastric cancer samples without a significant correlation with clinicopathological features, such as patient age or sex, tumor location, depth of tumor invasion and lymph node metastasis52. Lee et al.,51 identified sequence alterations in D-loop region (mostly in D310) of mtDNA in 51.6% of gastric cancer samples. According to their data, 54.8% of the gastric cancers had 3. Conclusion Mutations in the mtDNA have been reported in almost all forms of primary tumors examined. As recently classified by Carew and Huang66, (1) the majority of the mutations are base substitutions; (2) mutations occur in all protein-coding mitochondrial genes; (3) the D-loop region is the most frequent site of somatic mutations across most tumor types; and (4) the presence of homoplasic mutant mtDNA in tumors suggests that they may play an important role in the development of tumors. 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Mol Cancer 2002; 1: 9. 67. Penta JS, Johnson FM, Wachsman JT, Copeland WC. Mitochondrial DNA in human malignancy. Mutat Res 2001; 488: 119-133. 136 MERKEZİ TIP EĞİTİMİ SINAVI (METES) Mehmet Ali Gülpınar Tıp Eğitimi Anabilim Dalı, Tıp Fakültesi, Marmara Universitesi, İstanbul, Türkiye ÖZET Tıp ve eğitim bilimlerinde görülen gelişmelerle tıp eğitimi programlarının yeniden yapılandırıldığı yeni süreçte, eğitim çıktısının (ürünün) karmaşık kazanımlar (performans) şeklinde belirlendiği işe dayalı (taskbased) kompleks öğrenme/ öğretim modelleri ön plana çıkmaya başladı. Bu dönüşüme paralel olarak ölçmedeğerlendirmede de, bilgi, beceri ve/ veya tutumu ayrı ayrı değerlendiren ölçme-değerlendirme yöntemlerine, bütüncül yaklaşımlar benimsenerek performansa ve yeterliliğe dayalı alternatif değerlendirme yöntemleri eklendi. Son yıllarda gelişmeler ışığında ülkemizdeki tıp eğitimi programları, amaç öğrenim hedeflerinden ölçme-değerlendirme yöntemlerine kadar tüm bileşenleri ile gözden geçirilmeye başlandı. Bu çerçeveden bakıldığında, sadece bilişsel alan hedeflerinin değerlendirildiği mevcut Tıpta Uzmanlık Sınavının yetersizliği nedeniyle bu yönde yeni arayışlara gidilmeye başlandı. Bu amaçla, Merkezi Tıp Eğitimi Sınavı ile ilgili rapor hazırlanarak Marmara Üniversitesi, Tıp Fakültesi, Araştırma, Planlama ve Koordinasyon Kurulunda tartışıldıktan sonra Üniversitelerarası Kurul’a sunuldu. Tüm tıp fakültelerinin katılımıyla, konu ile ilgili tartışmaları yaygınlaştırmak amacıyla söz konusu rapor bu metinde değiştirilmeden verildi. Anahtar Kelimeler: Tıpta uzmanlık sınavı, Merkezi sınav, Tıp eğitimi, Ölçme-değerlendirme NATIONAL BOARD OF EDUCATION IN MEDICINE ABSTRACT As a result of new developments in the fields of medicine and of education, a report was drawn up by the Marmara University, School of Medicine, Committee of Investigation, Planning and Coordination of undergraduate medical education. This report was presented to the Council of Higher Education, Interuniversity Council. Keywords: National board, Medical education, Assessment alınmaya ve somut yaşantılar üzerinden yapılandırılmaya başlandı1-5. Eğitim çıktısının (ürünün) karmaşık kazanımlar (performans) şeklinde belirlendiği işe dayalı (task-based) kompleks öğrenme/ öğretim modelleriyle, ölçme-değerlendirmede de bütüncül ve karmaşık yaklaşımlar benimsenerek, performansa ve yeterliliğe dayalı alternatif değerlendirme yöntemleri gündeme geldi6-9. GİRİŞ Son yıllarda tıp ve eğitim bilimlerinde gözlenen gelişmeler, tıp fakültelerinde uygulanan eğitim programlarının, ölçme değerlendirme sistemleri de dahil olmak üzere tüm bileşenleriyle yeniden yapılandırılmasını gündeme getirdi. Bu gelişmelerle, önceleri daha çok konu merkezli olan eğitim programları, problem çözmenin öne çıktığı ve değişik derecelerde de olsa öğrencinin merkeze alındığı öğrenci-merkezli, disiplinlerarası entegre eğitim programları yönünde değişmeye, öğrenme ve öğretim, kendi bütünlüğü ve karmaşıklığı içinde ele Eğitim ve tıp dünyasında yaşanan bu çok boyutlu gelişme, ülkemizde bulunan tıp fakültelerine değişim ve dönüşümü bir zorunluluk olarak dayatmaya başladı. Ayrıca, yıllardır devam eden ve son yıllarda açılan İletişim Bilgileri: Mehmet Ali Gülpınar MÜTF, Tıp Eğitimi, İstanbul, Türkiye e-mail: mgulpinar@marmara.edu.tr Marmara Medical Journal 2007;20(2);137-143 137 Marmara Medical Journal 2007;20(2);137-143 Mehmet Ali Gülpınar Merkezi tıp eğitimi sınavı (metes) hedeflerinden, özellikle kavrama, uygulama ve analiz düzeylerine yoğunlaşarak hazırlanacak disipliner ve disiplinler arası çoktan seçmeli sorularla yapılacak değerlendirme, temel ve klinik bilimlerin kavram ve ilkelerin kavranması, entegrasyonu, kliniğe uygulanması ve klinik olguların analizine yönelik olacaktır. yeni tıp fakülteleriyle birlikte daha da belirginleşen, ‘tıp eğitiminde ulusal düzeyde bir standardizasyonun sağlanması’ konusunun hala önemli bir problem alanı olarak varlığını sürdürmesi nedeniyle, Üniversitelerarası Kurul’da gündeme gelen sınav sistemi ile ilgili değişiklik önerisi tartışmaya değer bulunuldu. Tüm tıp fakültelerinin katılımıyla gerçekleşecek tartışmaya katkıda bulunmak amacıyla aşağıdaki rapor hazırlanarak fakültemizin ilgili kurulunda görüşüldükten sonra Üniversitelerarası Kurul’a sunuldu. Merkezi Tıp Eğitimi Sınavı (METES) ile ilgili tartışmaların artarak devam etmesinin gerektiği düşünüldüğü için, Üniversitelerarası Kurul’a sunulan bu rapor metnin devamında değiştirilmeden verildi. A. S na · Temel ve klinik tıp bilimlerinin temel kavram ve ilkelerini kavrama derecesini ve temel ve klinik bilimler arasındaki entegrasyonu değerlendirme · Sosyo-psikolojik ve çevresel bağlamda, kişisel, sosyo-kültürel ve ekonomik özellikler ile etkin iletişimin ve etiğin temel ilkelerini gözeterek, temel kavram ve ilkeleri kliniğe uygulama ve klinik olguları analiz etme derecesini değerlendirme MERKEZİ TIP EĞİTİMİ SINAVI İÇİN TASLAK Altı yıllık tıp fakültesi eğitimini değerlendirmek ve mezuniyet sonrası eğitim programlarına yerleştirmeleri yapabilmek amacıyla METES ile ilgili iki plan hazırlandı. Toplam üç sınavdan oluşan A planında öğrenci, üçüncü ve beşinci yılın sonundan itibaren, istediği zaman, iki bilgi sınavı ve intörnlük sonrasında bir beceri sınavına girecektir. Sınav sayısının iki olduğu B planında ise, öğrenci bilgi sınavına beşinci yılın sonunda, beceri sınavına ise intörnlük sonrasında girebilecektir. Öğrencinin kendi fakültesinden mezuniyetini etkilemeyecek olan bu sınavlar hekim adayının işe başlayabilmesinde, doktora veya uzmanlığına yerleştirilmesinde belli oranlarda etkili olacaktır. · Bilimsel yaklaşım ve problem çözme ile ilgili bilgi ve beceriler ile, bunların klinik olgulara uygulamalarını değerlendirme B. S nav n Kapsam ve Düzeyi: Aşağıda sınavın kapsamı ana başlıklar halinde verilmiştir. Ulusal düzeyde oluşturulacak çalışma komisyonlarıyla her bir başlıkla ilgili yeterlilikler ve değerlendirme kriterleri belirlenecektir. Bunun için öncelikle ulusal tıp eğitiminin genel amaçları ile genel ve özel hedeflerinin belirlenmesi, ulusal çekirdek eğitim programı (ÇEP)’nın oluşturulması ve toplumun sağlık profili ile ilgili verilerin (en sık görülen, en çok sakat bırakan veya öldüren hastalıklar gibi) değerlendirilmesi gerekir. Yeterlilik ve değerlendirme kriterlerinin belirleneceği beş ana başlık: A PLANI Bu plana göre tıp fakültesi eğitimi süresince öğrenci, üçüncü yılın sonundan itibaren I. Basamak Temel ve Klinik Bilgi sınavına, beşinci yılın sonundan itibaren II. Basamak Klinik Bilgi Sınavına ve İntörnlük sonrasında ise II. Basamak Klinik Beceri Sınavına girecektir. I. BİRİNCİ BASAMAK TEMEL VE KLİNİK BİLGİ SINAVI 1. Etkin iletişim, 2. Moral bağlam ve etik değerlendirme, 3. Sosyo-psikolojik bağlam, 4. Temel ve klinik bilgi/beceriler ve kliniğe uygulaması, 5. Bilimsel yaklaşım ve problem çözme becerisi 10,11 Yılda iki defa yapılacak bu sınava öğrenci üçüncü yılı bitirmek şartıyla istediği zaman girebilecektir. Bilişsel alan Düzey: Bilişsel alan hedefleri: kavrama-uygulama-analiz-sentezdeğerlendirme1 138 Bilgi- Marmara Medical Journal 2007;20(2);137-143 Mehmet Ali Gülpınar Merkezi tıp eğitimi sınavı (metes) klinik olguları biyo-sosyo-psikolojik bağlam içinde analiz etme ve çözüm önerileri getirme bilgi/becerisini (tanı ve tedavi protokolleri oluşturma) değerlendirme B. S nav Kapsam ve Düzeyi Yeterlilik ve değerlendirme kriterlerinin belirleneceği beş ana başlık: 1. Etkin iletişim, 2. Moral bağlam ve etik değerlendirme, 3. Sosyo-psikolojik bağlam, 4. Temel ve klinik bilgi/beceriler ve kliniğe uygulanması, 5. Bilimsel yaklaşım ve problem çözme becerisi Düzey: Bilişsel alan hedefleri: Bilgi-kavramauygulama-analiz-sentez-değerlendirme1 C. S nav n Yap land r lmas : Sınav iki bölümden oluşacaktır 12,13: 1. Sağlık ve hastalıkla ilgili temel kavram ve ilkeler: İçerik: Büyüme, gelişme, genetik, yaşlanma, immün sistem, stres vb disiplinlerarası konularla ilgili kavram ve ilkeler Soru Teknikleri: Çoktan seçmeli sorular - En uygun şık, eşleştirme vb soru tipleri 2. Organ Sistemleri (Klinik Disiplinler) ve Hastalıkları: a) Koruyucu hekimlik İçerik: Klinik epidemiyoloji, biyositatistik ve araştırma tekniklerin kliniğe uygulanması, klinik sosyoloji ve sağlık ekonomisinin kavram ve ilkeleri, klinik olguların bu açılardan analizi ve klinik problemlerin çözümü b) Tedavi edici hekimlik İçerik: Organ sistemleri bazında klinik bilimlerin kavram ve ilkeleri, normal ve patolojik süreçler (etiyoloji, patofizyoloji prognoz), psiko-sosyal, çevresel ve moral bağlam içinde klinik olguyu analiz etme ve çözüm önerileri oluşturma C. S nav n Yap land r lmas : Sınav iki bölümden oluşacaktır12,13: 1. Temel ve klinik bilgiler: İçerik: Disipliner (fizyoloji, mikrobiyoloji vs) ve disiplinlerarası (genetik, immün sistem, beslenme, büyüme gelişme, stres vs) düzeyde temel kavram ve ilkeler, normal ve patolojik süreçler, tedavi ilkeleri, tanı yöntemleri, etik ve psikososyal kavram ve ilkeler Soru teknikleri: Çoktan seçmeli sorular - En uygun şık, eşleştirme vb soru tipleri 2. Organ sistemleri ve hastalıkları: a) Koruyucu hekimlik – İçerik: Klinik epidemiyoloji, biyoistatistik ve araştırma teknikleri, koruyucu hekimlik uygulamaları vb b) Tedavi edici hekimlik - İçerik: Temel ve klinik bilimin entegrasyonu ve kliniğe uygulaması; normal ve patolojik süreçler (etiyoloji, patofizyoloji, prognoz); tedavi ilkeleri ve tanı yöntemlerinin seçimi, uygulaması. Bilimsel yaklaşımla, etik, psikososyal, çevresel ve kültürel bağlamı da dikkate alarak, klinik olgu ile ilgili problem çözme becerisinin değerlendirilmesi (klinik olgu analizi). Soru teknikleri: Çoktan seçmeli sorular Örnek olgu, eşleştirme vb soru tipleri II. İKİNCİ BASAMAK KLİNİK BİLGİ SINAVI Yılda iki defa yapılacak bu sınava öğrenci, beşinci yılı bitirmek şartıyla istediği zaman girebilecektir. Disipliner ve disiplinlerarası çoktan seçmeli sorularla yapılacak değerlendirme, daha çok klinik bilimlerin kavram ve ilkelerini uygulamaya, klinik olguları analiz etmeye ve tanı ve tedavi protokolleri oluşturmaya (sentez) yönelik olacaktır. A. S nav n Amac : · Temel ve klinik tıp bilimleri arasındaki entegrasyonu, · Kişisel ve sosyo-kültürel özellikler ile, etkin iletişimin ve etiğin ilkeleri gözeterek, hastamerkezli yaklaşımla temel kavram ve ilkelerin kliniğe uygulama derecesini ve · Problem çözme basamaklarını ve bilimsel metodolojiyi kullanarak, bütüncül yaklaşımla c) Hekimlik uygulamaları İçerik: Hikaye alma, fizik muayene, tanı yöntemleri, hastalığın derecesini değerlendirme, tedavi ve takip protokolü belirleme, koruyucu hekimlik uygulamaları Soru Teknikleri: Çoktan seçmeli sorular - En uygun şık, örnek olgu, eşleştirme vb soru tipleri 139 Marmara Medical Journal 2007;20(2);137-143 Mehmet Ali Gülpınar Merkezi tıp eğitimi sınavı (metes) III. İKİNCİ BASAMAK KLİNİK BECERİ SINAVI açısından, merkezde hazırlanan rubriklerle değerlendirilecektir: İntörnlüğün bitiminde yapılacak bu sınav yılda 2-4 defa yapılabilir ve pratisyen hekimliğe başlamada baraj olarak kabul edilir. Sınavlar merkezden belirlenen uzmanların gözetiminde değişik bölgelerde kurulacak ölçme değerlendirme merkezlerinde (Örneğin Türkiye geneli 6-7 bölgeye ayrılarak buralardaki üniversitelerde ölçme değerlendirme merkezleri kurulanabilir) hasta simulasyonlarıyla veya tüm eğitim hastanelerinde hasta rızası alınarak yapılabilir. Bu sınavları standardize etmek için merkezde hazırlanan değerlendirme formları kullanılmalıdır. Ayrıca intörnlük dönemi rotasyonlarını standardize etmek için, intörnlük dönemi özel hedefleri ile yeterlilik ve değerlendirme kriterleri dikkate alınarak rotasyonlarda kullanılmak üzere merkezi komisyonlar tarafından gözlem, takip, düzeltme/iyileştirme ve rotasyon sonu değerlendirme formları hazırlanmalıdır. Bu formlar kurumlar ve kişilere mekan konusunda esneklik sağlar. Kişisel istekler veya kurumların söz konusu rotasyonlar için koşulları göz önünde bulundurularak, eğitim hastaneleri olmak şartıyla, öğrenci uygun yerlere yönlendirilebilir. 1. Psiko-sosyal, çevresel ve moral bağlamda ele alınan klinik vakanın tanımlanması, problemin odaklanması, analizi, çözümü, değerlendirilmesi, sürecin etkin bir şekilde takibi ve yönetimi, hasta ve hasta yakınlarının doğru ve yeterli bilgilendirilmesi. analitik 2. Pratisyen hekimlik uygulamaları: Hikaye alma, fizik muayene, tanı yöntemleri, hastalığın derecesini değerlendirme, tedavi ve takip protokolünün belirlenmesi, rapor hazırlama ve dosyalama C. S nav Kapsam ve Düzeyi: Yeterlilik / değerlendirme belirleneceği altı ana başlık: kriterlerinin 1. Etkin iletişimi, 2. Moral bağlam ve etik değerlendirme, 3. Sosyo-psikolojik bağlam, 4. Temel ve klinik bilgi/beceriler ve kliniğe uygulanması, 5. Bilimsel yaklaşım ve problem çözme, 6. Kişisel farkındalık, rol seçimi ve profesyonellik 10,11 Düzey1: Bilişsel alan hedefleri: Bilgi-kavaramauygulama-analiz-sentez-değerlendirme Devinsel (psikomotor) alan hedefleri: Algılama-kurma-rehberle yapma-uyarlamayaratma Duyuşsal alan hedefleri: Algılama-ilgi duyma-değer verme-düzenleme/örgütlemekarakterize etme. A. S nav n Amac : Karmaşık beceri ve karmaşık öğrenme/ bütüncül öğrenme ilkelerine göre oluşturulmuş simüle olgular veya hastalar üzerinden, psiko-sosyal ve moral bağlam içinde, klinik bilgi ve becerileri uygulama, tanıya gitme, tedavi protokolü oluşturma ve takip gibi hekimlik uygulamalarını yeterliliğe dayalı (pratisyen hekimlik düzeyinde) olarak performans üzerinden değerlendirme5-10. B PLANI Bilgi ve becerinin değerlendirildiği iki sınavdan oluşan B Planında öğrenci Temel ve Klinik Bilgi Sınavına beşinci yılın sonundan, Klinik Beceri Sınavına ise intörnlüğü bitiminden itibaren girebilecektir. B. S nav n Yap land r lmas : Poliklinik (ayaktan bakım ve tedaviyle ilgili bilgi ve becerileri değerlendirmek için), servis (kronik hastalıklarla ilgili bilgi ve becerileri değerlendirmek için) ve acil ortamlarda geçen simüle hastalarla (veya bilgisayar destekli simülasyonlarla), adayın performansı (bilgi, beceri ve tutum) pratisyen hekimlik (I. Basamak Sağlık Hizmetleri açısından) düzeyinde aşağıda sıralanan noktalar I. TEMEL VE KLİNİK BİLGİ SINAVI Yılda iki defa yapılacak bu sınavda değerlendirme genel olarak temel ve klinik bilim kavram ve ilkeleri ile, bunların entegrasyonu, kliniğe uygulanması, klinik olguların analizi ve klinik problemlerin çözümüne yönelik (tanı ve tedavi protokolleri) olacaktır. 140 Marmara Medical Journal 2007;20(2);137-143 Mehmet Ali Gülpınar Merkezi tıp eğitimi sınavı (metes) formalarıyla yapılan değerlendirmelerin toplandığı bir intörn dosyası oluşturulacaktır (portfolyo ile değerlendirme)1. Bu dönemde öğrenciler, kurumsal ve ulusal ÇEP’e göre belirlenecek bazı önemli klinik beceriler açısından yeterliliğe dayalı olarak değerlendirilecek (Örnek. Kadın doğumda en az 2 doğum katılma, 3 Jinekolojik muayene yapma vb) ve bu sırada kullanılan gözlem formları intörn dosyasına eklenecektir6. A. Amaç, S nav Kapsam ve Düzeyi: (Bakınız, A planı II. Basamak Klinik Bilgi Sınavı) B. S nav n Yap land r lmas : Organ sistemleri bazında yapılacak sınav üç bölümden oluşur: 1. Sağlık ve hastalıkla ilgili temel kavram ve ilkeler: İçerik: Büyüme, gelişme, genetik, yaşlanma, immün sistem, stres vs gibi interdisipliner konular ile ilgili kavram ve ilkeler Soru Teknikleri: Çoktan seçmeli sorular - En uygun şık, eşleştirme vb soru tipleri 2. Temel ve Klinik Tıp Bilimleri: Disiplinlerle ilgili sorulardan oluşur a) Temel Tıp Bilimleri: Temel bilimlerle ilgili kavram ve ilkeler, normal ve patolojik süreçler b) Klinik Tıp Bilimleri: · Koruyucu hekimlik TEMEL TIP BİLİMLERİ DOKTORASI VE KLİNİK UZMANLIĞA YERLEŞTİRME Tıp fakültesi seçenekler: öğrencilerinin önündeki 1. Pratisyen Hekimlik: Merkezi bilgi sınavı/sınavlarında belli bir puan alan ve klinik beceri sınavında yeterli bulunan öğrenci mezuniyet sonrasında pratisyen hekim olarak iş hayatına atılır. 2. Klinik Uzmanl k Eğitimi: Altı yılın sonunda mezun olan öğrenci, dosyası ile birlikte klinik uzmanlık eğitimlerine yerleştirilmek üzere başvurur. Yerleştirme, yılda iki defa yapılacak merkezi yerleştirme ile veya fakültelere doğrudan başvurular ile iki türlü olabilir. 3. Temel Bilimler Doktoras : Beşinci yılın sonunda yapılan klinik bilgi sınava giren öğrenci dosyasıyla başvuruda bulunabilir. İntörnlüğü tamamlaması ve klinik beceri sınavına girmesi gerekmez. Yerleştirme yılda iki defa merkezi olarak veya fakülteler tarafından doğrudan yapılabilir. Öğrencinin hekimlik hakları saklıdır, daha sonra hekimlik yapmaya karar veren kişi intörnlük rotasyonlarını tamamlamak zorundadır. İçerik: Klinik epidemiyoloji, biyositatistik ve araştırma tekniklerin kliniğe uygulanması, klinik sosyoloji ve sağlık ekonomisinin kavram ve ilkeleri, klinik olguların bu açılardan analizi ve klinik problemlerin çözümü · Tedavi edici hekimlik İçerik: Organ sistemleri bazında temel kavram ve ilkeler, normal ve patolojik süreçler (etiyoloji, patofizyoloji prognoz), psikososyal, çevresel ve moral bağlam içinde klinik olguyu analiz etme ve çözüm önerileri oluşturma · Hekimlik uygulamaları İçerik: Hikaye alma, fizik muayene, tanı yöntemleri, hastalığın derecesini değerlendirme, tedavi ve takip protokolünün belirleme, koruyucu hekimlik uygulamaları Öğrenci dosyas nda bulunacaklar; Soru Teknikleri: Çoktan seçmeli sorular - En uygun şık, örnek olgu, eşleştirme vb soru tipleri a. Bitirdiği fakültede yapılan 5-6 yıllık değerlendirmelerin sonuçları b. Merkezi bilgi sınavı/sınavlarının sonuçları c. Klinik uzmanlık başvuruları için intörn dosyası (temel bilimler doktora başvurusunda istenmez) d. Klinik uzmanlık başvuruları için Klinik Beceri Sınavının sonucu (temel bilimler doktora başvurusunda istenmez) e. Yabancı dil sınavı II. KLİNİK BECERİ SINAVI (Bakınız A Planı II. Basamak Klinik Beceri Sınavı) İNTÖRNLÜK DÖNEMİ İki-üç aylık rotasyonlardan oluşan intörnlük döneminde her öğrenci için, merkezde hazırlanmış yeterliliğe dayalı intörn izleme, takip, düzeltme/iyileştirme ve değerlendirme 141 Marmara Medical Journal 2007;20(2);137-143 Mehmet Ali Gülpınar Merkezi tıp eğitimi sınavı (metes) · Bu değişiklikleri kapsayacak şekilde gerekli alt yapı düzelmelerinin yapılması: Klinik uygulama laboratuarı, ölçme değerlendirme laboratuarı, araç-gereç ve kaynaklar · Uzman kişilerin eğitimi ve istihdamı. Bu amaçla Tıp Eğitimi AD kadrosunun en kısa zamanda şu uzmanları içerek şekilde zenginleştirilmesi: Program Geliştirme ve Değerlendirme Uzmanı, Ölçme Değerlendirme Uzmanı, Klinik Sosyolog ve Psikolog vb DEĞERLENDİRME VE SONUÇ Merkezi Tıp Eğitimi Sınavı öncesinde ÇEP ile uyumlu eğitim programının oluşturulması, değerlendirme/yeterlilik kriterlerinin belirlenebilmesi ve uygulamaya başlanabilmesi için kurumsal ve ulusal düzeyde yapılması gerekenler ana başlıklar halinde şu şekilde sıralanabilir: · Ulusal düzeyde tıp eğitimi programlarını standardize etmek için çalışma ve ölçme değerlendirme komisyonlarının oluşturulması · Ulusal düzeyde tıp eğitiminin amacının, genel ve özel hedeflerinin belirlenmesi · Ulusal ÇEP’in son haline getirilmesi · Bu hedefler doğrultusunda, ulusal ve kurumsal ÇEP ile toplumun sağlık profilini dikkate alarak (en sık görülen, en çok öldüren ve sakat bırakan hastalıklar) klinik öncesi tıp eğitimi (1-3. sınıflar), klinik tıp eğitimi (4-5. sınıflar) ve intörnlük eğitiminin yeterliklerinin belirlenmesi · Söz konusu yeterliklere dayalı değerlendirme kriterlerinin belirlenmesi, hazırlanacak belirtke tablosu ile soruların dağılımlarının ve soru tekniklerinin belirlenmesi. · Değerlendirme kriterlerine göre yeterliliğe dayalı gözlem, takip, düzeltme ve değerlendirme formlarının hazırlanması, · Soru bankasının oluşturulması · Uzman kişilerin yetiştirilmesi, istihdamı · Değerlendirmeye uygun teknik alt yapının sağlanması (belli üniversitelerde ölçme değerlendirme merkezlerin kurulması gibi), · Tıp fakülteleri arasındaki koordinasyonun sağlanması, fakültelere, planlanan düzenlemeleri yapabilmeleri için gerekli desteğin sağlanması · Değişiklikler için gerekli yasal düzenlemelerin yapılması Tıp Fakülteleri düzeyinde; · Kurumsal ÇEP’in oluşturulması · Çalışmaların sürdürülmesi ve devamlılığının sağlanması için öğretim programı danışma ve çalışma grupları ile ölçme değerlendirme gruplarının oluşturulması · Fakültenin genel ve özel hedeflerinin belirlenmesi; klinik öncesi, klinik ve intörnlük dönemi öğretim programlarının hazırlanması, değerlendirme kriterlerinin belirlenmesi Son olarak, eğitim programının bütün bileşenlerinin bütün olarak ele alınması gerekir. Bu nedenle bir programla ilgili değerlendirme sistemi oluşturulurken program, analiz aşamasından öğretim tasarımı, uygulaması ve değerlendirmesine kadar, genel amaçlarından, hedeflere, öğrenme/öğretme yaşantılarına ve değerlendirme yöntemlerine kadar bütün bileşenleri bir arada düşünülmelidir. Özellikle, 2-3 yıllık ciddi bir hazırlığı gerektiren (ÇEP ile uyumlu programa geçmeden önce) analiz aşamasının sıkıştırılmasıyla erkene alınacak her uygulama, zaman içinde ciddi sıkıntı ve aksamalara neden olabilecek ve belki de 5-6 yıl içinde büyük çaplı değişimleri yeniden gündeme getirebilecektir. Ayrıca bu zaman, gerekli alt yapı desteğinin sağlanması ve henüz çok yeni olan tıp eğitimi anabilim dallarında öğretim elemanı kadrolarının sayı ve nitelik açısından yeterli bir düzeye gelebilmesi için de gereklidir. KAYNAKLAR 1. 2. 3. 4. 5. 6. 142 Gür MT. Araştırma ve eğitimde disiplinler arasılık. Eğitimin Geleceği. Üniversitelerin ve Eğitimin Değişen Paradigması (Editör Babüroğlu, ON.) içinde. 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