Marmara Medical Journal

Transkript

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 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: [email protected]
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 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
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.
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: [email protected]
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: [email protected]
Marmara Medical Journal 2007;20(2);66-74
66
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
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
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
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)
5 (100,0)
Yönetim
Çalıştığı bölüm-grup, n (%)
6 (10,8)
37 (89,7)
Kurşun işlenen bölümler
6 (100,0)
p<0,001**
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
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
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
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
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
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
75
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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
Yasar Beduk, et al.
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.
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Miyomoto H, Chang C. Antiandrogens fail to block
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Schröder FH. Endocrine treatment of prostate cancerrecent developments and the future. Part 1: MAB, early
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Eisenberger MA, Blumenstein BA, Crawford ED, et al.
Bilateral orchiectomy with or without flutamide for
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Tyrrell CJ, Kaisary AV, Iversen P et al. A randomized
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Iversen P, Tyrrell CJ, Kaisary AV, et al. Casodex
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multicenter randomized trials at a median follow-up of 4
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26. Goldenberg SL, Bruchovsky N. Use of ciproterone
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27. Pavone-Macaluso M, de Voogt HJ, Viggiano G., et al.
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acetate in the treatment of advanced prostatic
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the European Organization for research on treatment of
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28. Moffat LE. Comparison of Zoladex, DES and CPA
treatment in advanced prostate cancer. Eur Urol
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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
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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
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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
Hatice Türe, M.D.
Marmara Üniversitesi Tıp Fakültesi, Anesteziyoloji ve Reanimasyon
A.D., Altunizade, İstanbul, Türkiye
85
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
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
Hatice Türe, et al
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
Hatice Türe, et al
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
Hatice Türe, et al
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
Hatice Türe, et al
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
Hatice Türe, et al
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
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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.
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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
Vildan Karpuz,M.D.
Chairman, Department of Pathology, School of Medicine, Istanbul
Science University,Istanbul, Turkey
92
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.
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
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
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
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
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.
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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
Esra Saatçı, M.D.
Çukurova Üniversitesi Tıp Fakültesi, Aile Hekimliği Anabilim Dalı,
Adana, Türkiye
98
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.
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
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
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
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
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.
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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
Meltem Uygur, M.D.
Marmara Üniversitesi,Tıp Fakültesi Hastahanesi, Kadın Hastalıkları
ve Doğum ABD, Altunizadde, İstanbul, Türkiye
104
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.
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
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
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
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
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
.Deniz Konya, M.D.
Department of Neurology, School of Medicine, Maarmara University,
Altunizade, Istanbul, Turkey
110
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
Deniz Konya, et al
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
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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.
Deniz Konya, et al
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.
Atike Tekeli, M.D.
Academic Hospital, Marmara University Foundation, Cardiovascular
Surgery, Istanbul, Turkey
114
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
Atike Tekeli, et al
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:
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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.
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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
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26.
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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
Prof. Tufan Tarcan, MD
Urology Department,School of Medicine, Marmara University
Hospital, Altunizade, Istanbul, Turkey
118
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
Yusuf Temiz, et al
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.
Yusuf Temiz, et al
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.
Ayşe Oytun Bayrak, MD
Ondokuzmayıs Üniversitesi, Nöroloji, Samsun, Türkiye
122
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
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
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
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
Prof. Dr. Ayşe Özer
MÜ Tıp Fakültesi, Tibbi Biyoloji, İstanbul, Türkiye
mail: [email protected]
127
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
Cenk Aral, et al
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
Cenk Aral, et al
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
Cenk Aral, et al
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
Cenk Aral, et al
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
Cenk Aral, et al
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
Cenk Aral, et al
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. It is noteworthy that depletion of
mtDNA is also reported in many kinds of
cancer67. As discussed above, in addition to
several case-control studies, there are various
in vitro studies concerning the molecular
mechanism(s) of these molecular alterations.
134
Cenk Aral, et al
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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:
MÜTF, Tıp Eğitimi, İstanbul, Türkiye
137
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-
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,
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
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
uygun şık, örnek olgu, eşleştirme vb soru
tipleri
139
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,
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
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
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;
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
· 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. İstanbul:
Sabancı Üniversitesi Yayınları, 2003: 181-209.
Gülpınar MA. Beyin/ zihin temelli öğrenme ilkeleri ve
eğitimde yapılandırmacı modeller. Kuram ve
Uygulamada Eğitim Bilimleri. 2005; 5(2):271-306.
Demirel Ö. Kuramdan uygulamaya eğitimde program
geliştirme. Ankara: Pegem A Yayıncılık, 2000: 111-170.
Harden RM. The integration ladder: A tool for
curriculum planning and evaluation. Medical Education.
2000; 34:551-557.
Van Merrienboer JJG, Clark RE, de Crook MBM.
Blueprints for complex learning: The 4C/ID-model.
Educational Technology, Research and Development
2002; 50(2):39
Linn RL, Gronlund NE. Mesaurement and assessment in
teaching. New Jersey: Merrill, Prentice-Hall, Inc.,
2000:259-313.
7.
8.
9.
Hager P, Gonczi A, Athanasou J. General issues about
assessment of competence. Assessment & Evalutaion in
Higher Education 1994;(19/1): 3-16.
Van der Vleuten CPM. The assessmnet of professional
competence: Developments, research and practical
implications. Advances in Health Sciences Education.
1996; 1:41-47.
Schuwirth LWT, Southgate L, Page GG, Paget NS,
Lescop JMJ, Lew SR, Wade WB, Baron-Maldonado M.
When enough is enough: a conceptual basis for fair and
defensible practice performance assessment. Medical
Education 2002; 36:925-930.
10. ACGME outcome project. General competencies.
Erişim
adresi
ve
tarihi:
Eylül
2002,
http://www.acgme.org/outcome/comp/compfull.asp.
11. The nine competencies. The Office of Medical
Education & Curricular Affairs. Indiana Universty,
School of Medicine. Erişim adresi ve tarihi: Eylül 2002,
http://meded.iusm.iu.edu/competencies/
12. United State Medical Licensing Examination. Erişim
adresi ve tarihi: Aralık 2002, . http://www.usmle.org
13. National Board of Medical Examiners. NBME programs
and services. Erişim adresi ve tarihi: Ekim 2002,
http://www.nbme.org/programs/medsch.asp#subjexam.
143

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