controversies in o&b and infertility (athens 14-17 april 2005)

8/16/2019 Controversies in O&B and Infertility (Athens 14-17 April 2005)

1/825

(Signature invalid, document altered) Signed by ... .... (Eli Oren) Time: 2005.03.20 12:29:30 +02'00' Reason: .....: .. .... .''.Controversies in ObstetricsGynecology and Infertility

Editors:

Z. Ben-RafaelG. CreatsasZ. ShohamOren Publisher Ltd.International Proceedings Division2005


2/825

Proceedings of the congress:

Controversies in ObstetricsGynecology and Infertility

Athens, Greece, April 14-17, 2005

Editors:

Z. Ben-RafaelG. CreatsasZ. ShohamOren Publisher Ltd.International Proceedings Division2005


3/825

Proceedings of the 7th world Congress Athens Greece. April 14-17 2005© Copyright 2005E. Oren Publisher Ltd.

All rights reserved. No part of this publication may be reproduced, stored inretrieval system, or transmitted, in any form, or by any means, electronic, mechanical,photocopying, recording or otherwise, without the prior permission, inwrithing, from the publisher.

Graphic Layout by E. Oren Ltd.E-mail: [email protected]

Printed in Israel by E. Oren Ltd. March 2005


4/825

Foreword

This is the 7th book of proceedings of Controversies in Obstetrics,Gynecology and Infertility, which summarizes the 7th World Congress inAthens, Greece. This book like the congress is solely devoted to controversialissues in the field and represents a unique source of cutting edgeknowledge for the general practitioner as well as for the expert.

As evident from the content of the book the controversies presented encompassthe main unresolved issues of our profession. The various chapterspresented here consolidate the knowledge through evidence-based medicinebut also indicate the gaps and lack of evidence to support certain clinicalpractices.

We believe that readers will find the chapters stimulating as a sourcefor updating their knowledge and helpful for practical handling of theirpatients.

Z. Ben-RafaelG. CreatsasZ. Shohamn


5/825

CONTENTS

But Surely Not Me: Snakes, Bugs and Us

C. O. Granai . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Gamete cryopreservation

Ovarian freezing -are we progressing? What are the gaps?María Sánchez. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Transplantation of cryopreserved ovarian tissue

J. Donnez, M.M. Dolmans, D. Demylle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36PCOS

Risks of Controlled Ovarian Hyperstimulation

Z. Ben-Rafael. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Why Give LH if FSH Works?

T. Child. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Overweight women: profertility effect of weight reduction.A prospective study

P.G. Crosignani, M. Colombo, W. Vegetti, E. Somigliana, A. Gessati, G. Ragni. .. . . . . . . . . . . 60Do we need insulin sensitizers?

B.C. Tarlatzis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Risks of ovarian stimulation

In vitro fertilization, ovulation induction and the risk of cancer

C.W. Burger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Is endometrial receptivity altered in COH cycles?

J. A. Horcajadas, C. Simón . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84Increased risks of health problems in singleton ART babies:Is it the procedure, the ovarian stimulation or infertility itself?

J. Cohen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Hot controversies in infertility

Why should we treat PCOS women with no infertility problem ?

L. Pawelczyk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95


6/825

Metformin and PCOS: Should they always go together?

E. Diamanti-Kandarakis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98


7/825

Controversies in Obstetrics, Gynecology and Infertility

Fresh ovarian tissue transplant: a propose of a place to implant it

A. Morales, G. Pons, O. Vidal, E. Treviño, D. Saldivar, L. Sordia, M. Merino,F. González, O. Barbosa, J. Vázquez. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102A structured literature review to establish the effectivityof metformin in the clomiphene-resistant patient

T. Siebert, T.F. Kruger, D.W. Steyn, S. Nosarka. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Pollution, infertility and carcinogenesis

Ecological aspects of Environmental Pollution, Focusing on Carcinogenesis

P. Nicolopoulou-Stamati.. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 118Other Health Hazards of Hormone Disrupters and how to fight them.

F. Comhaire, W. Dhooge, A. Mahmoud . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 130Impact of the environment on reproductive health: a bitter lesson from Athens

D.A. Adamopoulos, E. Koukkou. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 137Ovarian stimulation

New trends in IVF. Is there any evidence?

J. Serna, A. Pellicer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Induction of monoovulatory cycles for assistedreproductive technology (ART)

P. G. Crosignani, E. Somigliana, M. Colombo, A. Riccaboni, G. Ragni . . . . . .

. . . . . . . . . . . 145Neuroendocrine aspects of amenorrhea related to stress

A.D. Genazzani, C. Lanzoni, C. Strucchi, H. Mehemeti, F. Ricchieri,M. Ngo Mbusnum, O. Gamba, . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 149IVF or surgery first?

Fibroids and IVF: Which Comes First?

B.W. Rackow, A. Arici, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162Treatment of tubal pathology or IVF?

J. Bontis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175Uterine septum resection or IVF -which comes first ?P.Céline, L. Pascale, J. Donnez . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 180

In vitro maturation


8/825

In vitro maturation of human oocytes, potential benefit of in vivopriming with FSH/hCG before aspiration and priming of the endometrium

A.L. Mikkelsen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188IVM as an alternative in poor and over responders.Hananel E.G Holzer, William M Buckett, Seang Lin Tan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Health status and development of children who are born after IVM

A. L. Mikkelsen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203


9/825

Hot controversies in Infertility

Investigation and Treatment of repeated implantationfailure following IVF and ET

E.J. Margalioth, T. Eldar-Geva, M. Gal, A. Ben-Chetrit. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 208Is There a Life for IUI after the Advent of ICSI?

M. Yemini , J. Hade, A. Birkenfeld. . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 224Does PGD help in patients with repeated IVF Failure?

G.B. Maroulis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229Factors affecting Frozen Embryo Transfer program

H. Hashim, F. Al Salman , A. Felemban, H. Al Fozan., S. Hassan, M. Bugnah . . .. . . . . . . . . 231The Use of Advanced Reproductive Technologies in Israel:Are the professional partners seeing eye to eye?

Y. Simon, B. Kaplan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . 237Review of non-surgical and surgical treatment, and the role of insulin-sensitizingagents in the management of infertile women with polycystic ovary syndrome

A.M. Saleh, H.S. Khalil . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 241The peritoneal fluid. A cause or a consequence of endometriosis?

J. Szamatowicz, P. Laudanski . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Should treatment with clomiphene citrate continue?What should we offer to failures?

A. Weissman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259Prevention of pregnancy failure in IVF

Aspirin and other adjuvants in assisted reproduction

S. Daya. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Prevention of multiple pregnancies attributable to IVF/ICSI

D. Loutradis, P. Drakakis, A. Makrigiannakis, A. Antsaklis . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

Embryo transfer

Luteal phase support in assisted reproductive technologies

S. Daya. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292New technology and techniques

Virtual Hysteroscopy to Submucosal Myomas


10/825

K. Isaka . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Immune testing in fertility practice: Truth or Deception?

C. Kallen, A. Arici . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305Sexual dysfunction

Vestibulitis-Conservative Treatment or Surgery?

J. Paavonen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319


11/825


Androgen insufficiency in women: Does it exist?

G. Mastorakos , C. Marios C. Markopoulos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Surgical practice

The ten steps vaginal-hysterectomy

M. Stark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344Laparoscopic hysterectomy: Should we remove the cervix?

J. Donnez, J. Squifflet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350Laparoscopic myomectomy/myolysis : To whom should it be proposed ?

P. Jadoul, J. Donnez. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 357Hot controversies in Gynecology

A new safer bipolar intelligent coagulation system

C. Wallwiener, E. Neunhoeffer, M. Wallwiener, R. Klein, M. Menger, M. Zubke. . . . . . . . . . . . 373Uterine artery embolization in the treatment of hemorrhagein obstetrics and gynaecology

J. Kowalski, R. Tarkowski, A. Nowakowski. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . 381In vivo proton magnetic resonance spectroscopy: A novel non-invasivediscriminatory test for ovarian tumors ?

E.A. Boss, R.D. Kok, D.W.J. Klomp, U.F.H. Engelke, H. Boonstra, R.A. Wevers,J.O. Barentsz, A. Heerschap, L.F.A.G. Massuger . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . 390Choriocarcinoma-ultrasonographic models

B. Nikolic, A. Mitrovic, V. Lackovic, B. Nikolic. . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . 395Screening and treatment of ovarian cancer

Prophylactic oophorectomy, salpingectomy and omentectomyin BRCA carriers with or without hysterectomy

P.E. Schwartz. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404Lymphadenectomy in Ovarian Cancer: A waste of time?

S. Fotiou. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410WHI Whats next?

HT and heart disease: Is it still an unsettled issue?

G.E. Christodoulakos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 415The million women study A critique


12/825


13/825

Prolonged use of OCs for symptomatic women

P.G. Crosignani . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430Adolescent contraception. Is there one solution?

G. Creatsas, A. Deliveliotou . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434Hormonal treatment for males and females

Hormone Therapy in 2005 for Men and Women: Where Are We?

M.J. Legato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443Hormone replacement therapy in the aging male and nutriceutical alternatives

F. Comhaire, A. Mahmoud. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447Hot controversies in Gynecology

Oophorectomy using hysterectomy At what age?The special case of endometriosis

A.E. Schindler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458Endometrial biopsy vs transvaginal ultrasound as a first line test in patientswith pathologically proven endometrial polyps

J.P. Lerner, D. Smok. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 463HIV infections in women How to deal with them?

T. Niemiec . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467Rationale for a safe alternative to conventional hormonereplacement therapy

D. Wildemeersch, D. Janssens, E. Schacht, K. Pylyser, N. De Wever . . . . . . .. . . . . . . . . . . . . 476Gender-based Medicine

How Sex Impacts Normal Human Function and the Experience of Disease

M.J. Legato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486Sleep disturbances -Why women are different from men?

Y. Dagan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491

The Impact of Gender on the Experience of Coronary Artery Disease

M.J. Legato . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496Urogynecology

Can SUI be treated medically? How to treat

A. Liapis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503


14/825

Endoscopy

Robotics in Gynecology Surgery

T. Falcone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513Laparoscopic Hysterectomy why is it not more popular

G. Pantos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517


15/825


Complications of Laparoscopic surgery-can they ever be eliminated?

T. Falcone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523High and low-risk pregnancies

Should all twins be delivered by cesarean section?

I. Blickstein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526Antepartum fetal surveillance in pregnancies complicated by diabetes mellitus

A.M. Vintzileos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532Second trimester miscarriage

Pregnancy loss: Evaluation and Treatment

A.M. Vintzileos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536The use of new ultrasonographic technologies in the evaluation

of uterine anomaliesG. Nazzaro, M. Locci, G. De Placido . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 540Clinical controversies in the management of Preterm Labor

Tocolytic efficacy what is the evidence?

K.S. Khan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542Fetal growth: Implication for perinatal care

Cerebral Palsy and Fetal Growth

B. Jacobsson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547Intrauterine growth in twin pregnancies

S. M. Kady, A. Francis, J. Gardosi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554Hot controversies in Obstetrics

Performances of dinoprostone slow release in the induction of labor

F. Facchinetti, P. Venturini, A. Volpe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

Use of b-lynch suture technique for postpartum haemorrhage acase report and review of literatureB.Vijayalakshmi, T.Doherty, P.Borrelli, D.Patil, S.F.Reynolds . . . . . . . . .. . . . . . . . . . . . . . . . 569

Growing importance of laparoscopic procedures during pregnancy

M. Klimek, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573Pre-eclampsia


16/825

The mode of delivery and Anesthesia in Preeclampsia

T. Sener . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578Prenatal screening and diagnosis

3D/4D: contribution to anomaly detectionor scan for parental entertainment?

N. Vrachnis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588


17/825

Ethics of First-Trimester Risk Assessment for Down Syndrome

S. T. Chasen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573Breast cancer

Consensus and controversies regarding screening for breast cancer.

P. Neven, E. Van Limbergen, C Van Ongeval, A. Van Steen. . . . . . . . . . . . . . . . . . . . . . . . . . . . 597Breast cancer and pregnancy

C. Markopoulos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610Hot controversies in Obstetrics

Neonatal sepsis after single vs. multiple coursesof antenatal betamethasone therapyS.Landolfo, S.Porcaro, A.Scarcella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

New objective method for the continuous assessment of fetal activity

K. Krzysztof, C. Krzysztof, K. Tomasz, S. Jacek, P. Tadeusz, L. Beata. . . . . . . . . . . . . . . . . . . . 620Intrauterine growth restriction, angiogenic factorsand their possible role in post-partum catch-up growth of the neonate

A. Malamitsi-Puchner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629Womens views of and preferences regarding three approachesto hospital care following first trimester miscarriage

J. Shelley, S. Grove , D. Healy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638Modification of preterm uterine contractile activity by inflammation:

Should we combine anti inflammatory drugs with anti-oxytocicsT. Laudanski, P. Pierzynski . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 644Does Antenatal Iron-deficiency Anemia Have an AdverseEffect on Pregnancy Outcome?

T.T. Lao, Ben C.P. Chan, Wing-Cheong Leung , Lai-Fong Ho . . . . . . . . . . . . . . . . . . . . . . . . . 650Thrombophilia in Obstetrics and Gynecology

Thrombophilia 2005 -Overview

T. Hatzis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656Thrombophilia: What is the evidence for the relation with adverse pregnancyoutcomes?

B. Brenner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665The value of LMWH treatment in OB/GYN

D. Blickstein. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


18/825

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673Emergency cases in pregnancy

Delivery of the impact fetal head: Instrumental vs. CS

I. Blickstein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678Condition-specific antepartum fetal testing

A.M. Vintzileos. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683


19/825



20/825

But Surely Not Me:Snakes, Bugs and Us

C. O. Granai, MDDirector, Program in Womens Oncology, Women & Infants Hospital/Brown University,Associate Professor, Brown University School of Medicine, Providence,Rhode Island [email protected]

Snakes, Bugs and Us; surely not me. Or is it the other way around? Odd title,wouldnt you agree? Meaningless? Possibly. In any case, thanks for consideringthe possibilities, and how we proceed when there are no answers. Once aftermaking a similarly obscure, oral presentation, I was invited to put aspects ofwhat was said on paper. My failed attempts to do so have curiously validatedone of the talks paradoxical, yet ironically unifying themes . . . having to dowith stumbling, if not falling flat on ones face; and then, what happens (next).The subject of this presentation is still not clear, is it?! How great the audacity,then, that leaving you in such unclearness, I nevertheless ask the honor ofyour (personal) company for the talk itself. But, your indulgence has beensought by my sort before, and youve always been kind. So, lets make a deal.Below are my above alluded-to editorials of August, 2003 and January,

2005, and a poem . . . they neednt be read, but if they are, their context may be best saved for after the oral presentation. The potential reading thing wouldbe your part of the deal. For my part, Ill do my best to make your April 15,Athens conference-morning colorful, dramatic, briefly sad, musical, and fun.Will the transaction be worth it? In the end, you be the judge . . . and you can tell me in no minced words. Thanks for the chance.


21/825


What Matters Matter?

(p-values, h-values, leadership and us)

Prhcis: As overwhelming as the dismay, anger and resignation are, is therereally no meaningful difference individual physician-leadership can make forpatients, health care, society, and doctors themselves?

Abstract: Framed by the question, what matters matter, the essay considerstodays tired physicians, their needed leadership, the historic, principled-roadthey embarked, and the reasons to continue. Taken as a whole, the vast problemsof health care are insolvable; but approached in small tangible steps, if not cure,could direction, even inspiration appear? When sick, people look to physicians.From their distinctive tradition of being present with patients, physicians have earned trust and learned, scientifically and artfully, about life in ways distant-others cannot. Homage to rational proof has separated physicians from alternatives,as homage to irrational human-values has distinguished them from pure

scientists. Both perspectives have proven vital since meaningful patient-centeredcare occurs at the brackish junction of logical science and tenuous humanneeds, p-values and h-values long compelling of physicians. Along with theprivileged understanding gained privately with patients, comes the responsibilityto stand publicly for the rights of all patients to private moments. Standingup in these ways can never be easy, then again, it never was. Its the continuedjourney towards historic ideals, somewhere in the paradox of mathematics andmystery. Its an imprecise place of struggle where caring leadership has alwaysbeen most needed, fulfilling and defining of physicians. And its there, despite todays insurmountable everything else, each physician will find ways tore-energize around what matters matter. Heres one way to consider

What is more important, science or art? the admired senior physician wasasked near the end. The Im not sure startled the junior prothgh. Why merelyconsider the reduced suffering brought by vaccines, antibiotics, anesthesia,surgery, Watson and Crick and randomized trials, and the answer is quicklyapparent the young doctor surmised.1,2,3,4 The old physician was less certain,instead quietly hoped for the sake of patients and the morale of doctors that achoice between the two would not have to be made.

Science or art? Sometimes equal sometimes not, doesnt it all depend? Butin this assuredly finite world, real limitations everywhere, the opportunity not to choose either/or is increasingly rare. In health care then, the germane questio

nbecomes: in choices of science or art, who chooses what matters matter?Many it would seem. Joining the fabled third parties are administrations, administrators,lawyers, medical bureaucrats, biostatisticians, consultants, regula


22/825

tors, fraud investigators, agencies, and numerous odd self-appointed multi-initialedcertifying groups.5 Flaunting threats and ever-pending missing-the-pointinspections, they choose, and worse, they dictate, though each is further andfurther removed, physically and experientially, from actual caring.6

But what about physicians, do they influence the debate on what mattersmatter too? While resisting a simple answer, todays convoluted health caresystem makes it easy for doctors to feel (and self-righteously cop) me, the individual physician, up against giant, powerful them; why thats a futilemismatch even Dr. Don Quixote would demur.7 From such a demoralizedmindset a fatal spiral naturally follows. Yet, as overwhelming as the dismay,frustration, anger and resignation are, is there really no meaningful difference individual physician-leadership can make for patients, heath care, society, andtheir own essential direction and self-worth? Remarkably, among the smallsteps-possibilities emerge values-based ruminations, like those perplexing thesenior doctor, about science or art and what matters matter.

Few are drawn to being a physician intending to forego art for science, orvice versa. Rather, physicians have offered what meager theyve known aboutboth, at difficult occasions of tandem medical and human need.8 Suddenly,however, does maintaining modern relevance require physicians to proceed

differently?9 Or, business school axioms on the essentialness of continuouschange aside, are some things, framing questions among them, timeless? 10

Silently asked each step along the way, introspective-questions like Whatwould you want done for your loved one under those circumstances? haveguided physicians to patient-centered recommendations evidence-based medicinealone never could/will.11 Found confronting lifes truly threatening healthproblems, most want the best of medical science and more.12 The more mightbe best understood as art, in any of its wide expressions including: unscientificlife-experience, intuitiveness, caring, touch, even weakness, failure andpoetry all part of elusive human values. Homage to inexplicable h-values has distinguished physicians from pure scientists, just as homage to rationalproof and evidence-based p-values has separated physicians from alternative

practitioners, philosophers, and bureaucrats.13, 14 Both perspectives have provedinvaluable, for the best patient-centered care seems to occur at the imprecisebalance of p-values and h-values, a brackish tenuous junction of logicalscience and less logical human needs long compelling of physicians.15

Few have been so honored to share in humanities uncertain moments, ashave physicians. From the eons of days and nights of being directly present, justthere, just then, physicians have gently earned trust. And from observationalscience physicians have come to learn about life, death, suffering and the


23/825


importance of time, in ways that the others who-would-choose-about-healthcare-on-behalf-of-patients cannot. Surely its not the case that only physicianssee, or for that matter all of any one group does. There are, of course, kind andvital people of all stripes working to make a difference. Seeking them out ispart of individual physician leadership.

Whether many or few, physicians can gratefully team with kindred-spiritsfrom nursing, social work, administration, trustees, CPAs, business leaders,third parties, politicians, and yes honest lawyers, to confront the macrolevel problems of health care. Only a team with shared ideals and diverseexpertise could hope to contend with such vast complexities, be they cynicalor unintended. One ailment ensnaring health care might analogously be dubbedf-values. Seemingly remote and less honorable than p and h values,financial-values are in reality critical to both. Without appropriate distributionof resources, including currently misaligned f-values, even the grandest ideaswill remain just that.

What would physician leadership bring the health care problem-solvingteam, skeptics will ask? Absurd on its face, the question must still be answered

:With proud tradition physicians bring the core that others cannot; the distinctivealternative of having learned scientifically and artfully from patientsnot fromthe abstract. Turning the question, is it conceivable that the best leadership of anygreat human endeavor could come from outside cum laude theorists, unbalancedby those rooted to the front-line? Can a journeyman trade be learned frombooks? Since the heart of health care is with patients, roots from that front-lineare fundamental to its best leadership. Roots alone, however, are not enough.

Lineage, in itself, is of perversely little value, if those so fortunate to have

it are otherwise swept away by the flow of popular currents. For example, in the momentary stream of medicine, it is difficult not to be overcome by a mathematical,biostatistical reverence so forceful as to submerge common sense. Could thisobfuscation explain why: knowing the literature, not the patient, is that most revered,rewarded and taught by academia. Another example of wayward politicalcurrents drowning reason is the one size fits all educational philosophy beingadvanced with an appeasing-arrogance by bureaucratic medicine. No matter thatSocrates himself was unable to do so, todays medical organizations, unbecominglydancing to the off-key music of outside fears, have obviously defined (andformatted) what education and work are including how long is too long.

Such silliness not withstanding, more concerning is that the unique value of lineage can be so easily nullified, with consequences remaining to be seen.

All the wounds in health care, however, are not self-inflicted. Entering thenegative mix largely from the outside are the, Im-not-sure-where-youve-hid


24/825

den-it-but-I-know-you-did-it-wrong-and-Ill-find-it, groups. These politicallysensitive rampaging agents believe in inscrutable and sanctimonious regulationfirst and foremost. More dubious yet is their zealous sense that fraud is the stealth overarching motivation for everything doctors do.16 Admittedly,these perspectives occasionally have their place. But, more often, when linearly applied by CMEs, IRBs, HICFA/CMS, HIPAA or as physician behaviorpolicies,17, 18 without context or exception, slowly passion, creativity, healthcare and society lose. And, in the midst of it all, is it any wonder why physiciansare tired, confused and demoralized in ways they cant fully understand.A call to action seems clear.

Always having been ready to stand privatelywith patients during their sacredmoments, more than ever physicians today are called to stand publiclyfor thesanctity of those same moments.19 Though a one-dimensional analysis reflexivelyjudges such moments too expensive, more fairly physicians know them tobe extraordinary human-instances defying economic quantification. They areincredible occasions where science and art imperfectly come together in serviceto people. Concerns about costs are dwarfed by the amazing good that can ripplefrom even a short time focused on lifes most meaningful things usually

otherwise deferred.20, 21 Medicine, flawed as it is, can facilitate (for patients andfamilies) the opportunity to reflect and take stock. Often this invokes a cominghome to old roads and rusted station wagons unwittingly traded for superhighwaysand slick turbos finally encountering toll booths, speed traps and flat tires.The special-chance to return, regardless of age, to say Im sorry or I loveyou is an elegantly simple, if unscientific, uneconomic, example of expensesjustified. But is an insight society only comes to have in time, one at a time.

Advocating for the rights to simple things, like lifes special chances, ispowerful physician-ship and in the reach of each physician. Standing againstshrill unseeing voices espousing armchair-conclusions deduced from trendycost: benefit formulas will never be easy however. But easy was never

promised as part of the high road physicians chose to embark. An incredibleroad it is nevertheless, where fortune holds that doing whats right is, at thesame time, uncommon (individual) leadership. Where humbly going forward,in service to others, in a world which can never be fully understood, is the mostearnest advocacy, and surely thats worth of celebrating.22

Naive? Jousting at windmills? Possibly so. But even in failure comes good,or so say the poets. They remind us that, win or lose, real peace resides in the meaningfulness of choices made and values stood for. For physicians the currentparadox is one of ethical, hard work and science beyond business; of mysteryand non-rational ordinary virtues elite statistical universities and the young


25/825


doctor prothgh cannot abide.23 It is a commitment to something bigger thanself, bigger even than math or sculpture, where ironically and without fanfareall the little things, scientific and not, add up as what matters matter.

P-values, h-values, leadership and us what can the individual physician do?

Contrary to any dark sounds, by its nature the potential for caring is undiminishable.How lucky physicians are to be able to believe in that future as wellas the patient-centered good they do now. Though the fog will never lift toclearly show the illogical curves ahead, this twisting road is nothing new forphysicians. Differing nuances era to era, sure, but in the greater sense todaysroad is the extension connecting physicians in time. Sensing this struggle asan experience in common is helpful, but even such profoundness cant totallyameliorate disorienting pain. Especially then, and for everyones sake, physicians need a simple means to remain grounded.

While tugging at the juggernaut of macro health care, it remains at themicro level, directly involving doctors and patients, where caring leadership

will always be most needed, fulfilling and defining of physicians. It is there where physicians will always find space to take measure and re-energize.Though ethereal in nature, this nourishing location can be made more cognizantwith paper and pencil, a dear colleague or two, a beautiful space, (and likely a glass of wine). Heres one way how

On a large sheet of paper create a ledger of a type most antithetical to theEnrons. Title the ledger what matters matter setting up two simple columns,one headed p-values the other h-values. Then, from your mind-of-scienceand heart-of-art, under the corresponding column fill in the blanks with thosetheorems, elements, data sets, therapies, trials, treatments, techniques, skills,

procedures, principles, concepts, values, ideals, metaphors, kindnesses, pillsand poems you would wish to bring the patients and families entrusting youwith their care. Sounds silly, its not. To the contrary, approached sincerely the experience is hard, if not at times scary and painful (but in the end gratifying).Its completion will be drawn from the totality of what you have come to knowscientifically, and from what you have come to believe truly important in life.When you are finished, along with some new, much of what is discoveredmay be that which brought you/physicians here in the first place. Either way,it is likely that if ledger sheets are compared, the p-values listed will differby medical discipline, but the h-values will hold much in common andreinvigorating of us all.


26/825

That certain age

Old, older, too old. A categorizing of age or of medical thinking about age?At different times and from the different vantages, like those of sincere caring,lesser technologies, and relative ignorance, patients of that certain age havebeen assumed non-candidates for certain treatments (i.e. that treatments risksare too much, benefits too little at thatage). Sometimes we have been rightin this, of course. But increasingly, when depending on arbitrary thinking, werenot. Further, and as Wrights article opens the door to considering, the consequencesof well-intended but misplaced assumptions could compromise thehealth of the very patients we wish to serve/protect. For reasons ranging fromevidence-based to philosophic, historically based pessimistic medical thinkingdeserves reassessment (1). While this continuously applies across medicine,the focus here will be oncology; along with perceptions of treatment-tolerancein the elderly, their spin-off implications, and other influences affecting cancertreatment decisions in older age groups. If the premises underlying current perceptionsare earnestly re-evaluated, it is likely the conclusion will be: contraryto traditionally held negative presumptions, the only thing certain is, we shoul

dno longer be so certain (2,3). Pragmatically, however, as it is with most truisms

(e.g. elderly patients do not do as well with cancer or cancer treatments), just considering alternative possibilities is hard enough; but translating them intoclinical behavior, well. thats an age-old high hurdle, made all the higherwhen the definitions, resources, and engulfing politics are constantly moving.First off, in 2004, what defines old? I will leave it to Wright et al todefend their definition of elderly as being from seventy years on. Sufficeit to say, there is ample room for social disagreement, and where the line isfinally drawn, will significantly affect the conclusions of any analysis. Anothe

rcogent yet amorphous, moving target is the definition of quality of life(4).With inferences to both, we receive sardonic crape-hanging milestone birthdaycards that proclaim ageits only a number. Still, and as those of us of thatcertain number soon come to know, in this linear world, numbers count, andcarry far-reaching impact, right and wrong (5). The stigma of the early-birdspecial,and corresponding service, or lack there of, seems instructive here.

True in all spheres of life, including medicine, the possibility of subtle influenceon (medical) decisions, caused by mere chronologic numbers, is notsomething to be casually dismissed. Though not sinister in origin, the ramificat

ionsof such influence can bring sub par results. Aware that ageism is everlurking how could it still happen in health care (2,3)? The reasons, obviouslycomplex, may start quite simply, in doctors being human, thus not immuneto the shallowness of culture and pop images celebrating revered-life as pos


27/825


sessing 20-year-old airbrushed skin and thick, non-grey Hollywood hair (i.e.definitions of old and quality-of-life compliments of Cosmo; a vanity thatsome in medicine also profit from as purveyors of expanding arsenals of youth-stimulating drugs and cosmetic surgery).

It would, however, be unfair to point accusatory fingers at dazzling mediaand reactionary consumerism as the prime explanations for medical distortionsabout age as a treatment criterion (6). Many elements, some occult, doubtlesslycontribute; and we, in medicine, are complicit in most, if only through passivity.Lets look at examples of negative influence taken from various categories,beginning with a seemingly facetious one close to home: the way we cliniciansformally communicate to each other about patients (but only to the extentHIPPA permits useful communication, needless to say). Everyday virtuallyevery case-presentation begins: Mr./Ms. X is a (insert number here) year oldpresenting with. There it is, right up front, the number, blazing with all thedrama afforded by juxtapositional primacy. How far behind could bias be?

So as not to be completely absurd, yes, in a general sense, age is animportant, long-recognized component in differentiating suitability for variousmedical and surgical managements. Obviously not all patients of any age are

candidates for all treatments (7). Aging brings well-documented changes inmultiple functional capacities (8), many having meaningful implications abouttreatment tolerance, quality of living, and life expectancy (9). But age is also non-specific. Whatever the shared number, it's clear that chronologicallyidentical people do not constitute a biologically homogeneous group (4,5).Some people at that age are physiologically younger, others of us older (10).Biologic context is critical in determining physiologic endurance, longevityand other matters for the individual patient (2). So too are the medical capabilitiesof the era and institution in question (11).

Even at this, there is much more that effects the therapeutic-choices made in

the care of elderly cancer patients. Physicians and hospitals are not alone in thatresponsibility. Negative stereotypes about age and treatments are deep andfar-flung. Paradoxically, some of the strongest pessimism coming into play isheld by the elderly themselves and their families (12). Whatever their origins,be it common sense, past realities, myths, stories from friends, depression, orordinary misinformation, each can narrow the vision of current potentials (13).Much of the hope for fairly re-balancing the score card relies on physicians educatingpatients, families, society, and ourselves, about the pros and cons of stateof-the-art treatments, along with their alternatives including the option of notreatment and its consequences (6). Maximal palliation is always a given.

Okay then, what is new in cancer care for the elderly? Fortunately a lot. For


28/825

instance, once insurmountable physiologic risk factors often accompanyingage, can now be proactively screened-for with CGA(comprehensive geriatricassessments) -like tools (14,15), diagnosed and accurately monitored before,during and after treatment (5,7). If encountered, such risks have relevance fortreatment, treatment modification, and outcome including survival. At the extreme,if the frailty syndrome is proven, it may preclude most semblances ofstandard cancer management (16,17). Fortunately, contrary to pessimistic stereotypicnotions, absolute contraindications to treatment are very rare. Further,the lesser risks that are more commonly present, though once limiting, aretoday resolvable or increasingly better managed thus affording effective cancerinterventions to go forward. Beyond the purely medical, we now recognizethat all constituencies have unique psychosocial-needs that must be addressedas well to maximize outcome. The elderly as a group are no exception, and theiroptimal oncologic care, which is the balance of so much, and much so unique,depends our learning about all and working to help in all areas. Contributingto the remarkable overall success are new insights, more specific and effectivetreatments with less toxicity, and an array of side-effect antidotes (18) and theprospective multidisciplinary team approach to oncology care . As they dotoday, stunning evolution in knowledge and technology will constantly alterthe risk:benefit ratio, opening unprecedented horizons for all ages.

Thus far so good, at least technically; but having new medical abilities, anddeciding to employ them, are two different things. The latter is less predictable,being nuanced by human behavior and what motivates and demoralizes it. Inthis vast world of forces, it is easy to understand why individual cliniciansfeel tiny and incapable of inspiring broad meaningful change. While somepower-venues do require larger organizational advocacy, the cry, let the ACSor ASCO handle it, is dangerously near a cop out. Rather, as the poets suggest,slowly each small thing adds up. Herein lies the call for personal involvementdespite few guarantees of conspicuous achievement. Since our own physician-behavior is the one thing we can predictably control, introspection informingpersonal vigilance, is a good and pragmatic place to begin.

Germaine to the implications of the Wright paper (where similar cancerpatients in different age groups often received different cancer treatments) inour reflective self-scrutiny, we should seriously wonder about what we do, if it differs from todays medical potentials (8). Every discrepancy between actionsand possibilities should be seen as a red flag marking the need for deeperdigging as to merit. Much of what personal exploration may find, is not likelyto be earth shaking, however (6). Indeed, compared to the shiny-commotion ofsuper medical technologies, or the drama of the smoking gun that exposes de


29/825


vious agendas, the relevant influences on individual behavior may seem, at first blush, small, insignificant, or rather silly. But, as fortune cookies aptly warn,left to their own devices, the mundane can mysteriously morph into insidious.The example of syntax in medical case presentations, may again pertain. In thatubiquitous medical construct, is age, per se, worthy of its headliner prominence,as if lifes foremost characteristic and/or determinant of treatment? Further,does having age so eminently sequenced, innocently create a quiet bias nowpart of the medical day-to-day? No! we would quickly voiceat least to thebias aspect; but is this being naive (19)? Either way, quasi-ageism finds waysinto health care from other quarters.

Joining the distortions of pervasive pop culture, subtle medical convention,and those held about themselves by the elderly, are other diverse influences.In the best of worlds, having additional thoughtful perspectives is invaluablein shaping health care (11). Under lesser ideal circumstances, the milieu of:healthcare, money, votes, and power, forms a perfect morass for demigodsand catastrophe. While different in origin and impetus, together the dispiritinfluences can dampen the likelihood of older patients receiving complex and

state-of-the art cancer treatments. Though at moments heart-felt and valid,at other times the opposition dubiously propagandizes todays best cancermodalities as not clearly superior or too aggressive sprouting anxietyand reluctance about that treatment; for who among us would self-inflictthose risky fates (11,20)?! An example of this deceptive posturing is seen incost-first priorities veiled as otherwise appropriate patient-centered concerns(20). Whatever the full motivation behind these espousals often made bynon-clinical groups (e.g. third parties, health care administrators, politicians),an intention to retard medical expense is usually part (19). Quite different istheir holistic public persona, however. Still, their bellicose thesis on economiccost, and its consequences, is a rightful concern to a society with limited

resources.Just beneath the specter of warm platitudes, their fiscal-reasoning about health care goes something like this. Since there is an inevitable and costly correlationbetween: aging, illness, health needs and dying; and because major fiscal expendituresfor medical treatment are not likely to be recouped from an elderly, anon-tax paying constituency; expensive (a.k.a. aggressive) interventions are bestinvested in a more youthful, longer-living stratum (20). Logical enoughtheyoung-eyed, one-dimensional, quick-fix, mathematician will conclude (21). A

factual deduction made only clearer from the abstract of never-having-sat-atthe-bedside. Yet if literally applied, beyond short-sighted and hurtful, such apolicy would be wrong on virtually all important counts (19).


30/825

This is not an argument against hospice. Depending on many factors,the fullness of supportive-care-only near the end of life can be a wise choicefor anyone (22). Still, in the example of the Wright paper, it is curious that thehospice-like, no treatment option, was selected nine-times more frequentlyby the older group. Empiric explanations, relating to: age, more advanced stageat diagnosis and otherwise more limited expectation, seems most plausible(23). Standing in opposition to the no treatment selection, are the effectivetherapies and long-term palliations now available, even for advanced stagecancer (19,24). Though once considered an anathema of medical care and ethics,today, formerly end stage cervical cancer patients primarily presentingwith urethral obstruction, are readily unblocked with minimum morbidity viainterventional radiology. The restored renal function then facilitates platinumchemotherapy alone, or more often as a radiation sensitizer. Compared to thedire outcomes of the past, let alone the consequences of no treatment, relativelysuperb results now follow present-day aggressive interventions (8).

Concerns about costs are important, nevertheless. They are not the proprietaryinterest of the non-medical community with their magnanimous balancedvision (25). To the contrary, all agree about the responsibility to engage finiteeconomic and medical resources, thoughtfully (26). But, in the spectrum of realhealth care needs, where are these assets more justly accorded than to the sick

(who are, by laws of nature and probability, often aged; not to mention theirhaving been long-paying taxpayers who similarly supported those precedingthem)? As for notions of return on investment, the cold question has manyvalidating retorts, none more fundamental than the humanistic inquiry in return: What is the value of living (to patients, family, and society; for six months, letalone six years)? Imperfect by many criteria, todays cancer management, evenwhen not literally curative, can allow people of all ages to live, in relative,if not excellent, quality; and, in that, have time to address all-too-forgottenpriorities. Sadly, this is more than most of us who die suddenly, will ever getaround to doing. What a wonderful difference this makes in the lives of realpeople, as can be readily seen in those left behind.

Standing for precious opportunities like this, is central to physician-ship andthe type of caring society we should want to live in. A society which is proudto invest its resources in human-needs, at the age/ time they actually occur.Yet, when it comes to investing in elderly cancer patients, optimal therapiesmay not rise to activation (27). This is cause for ongoing concern and introspectionabout validity, priorities, complicity, and change (21). While thereis no absolution, amid the harsh mix of diverse negative influences and olddata, understandably physician-perceptions about what treatments to suggest


31/825


at certain ages may be misaligned with the best of today. This stark possibility is Wrights indirect red flag for us.

Purportedly just another paper cataloging cervical cancer treatments andtheir tolerance in different cohorts a worthy endeavor in itself the studysmore far reaching value is in stimulating contemplation about the findings.Specifically, what accounts for the: lower rates of surgery, lower doses ofradiation, less use of adjuvant therapy, higher rates of post-treatment persistentdisease, and the previously mentioned more frequent opting of notreatment, all by the studys similarly-staged elderly sub-group? Like otherauthors, Wrights data shows that many older patients can successfully endurecomparable oncologic interventions (8,28,29). Despite their proven treatment-tolerance, the older patients frequently underwent different, typically lesser,cancer treatments. Among the multifactorial reasons behind the variation,some may be attributable to the studys duration (1986-2003). After all, thevalue and superiority of using sensitizing chemotherapy with radiation inadvanced cervical cancer, was not finally established until 1999, thirteen years into Wrights data base. Another reason for the studys lopsided treatment

distribution is ascribed to enrollment onto prospective protocols that dictatedtherapy. There are, undoubtedly, many medically sound reasons behindthe treatment-choices made here, or anywhere in general. More importantyet is the patients preeminent right to choose any way they wish; and thatas physicians we accept, that true to human nature, subjective reasoning willoften trump objective (30). All this being so, the nagging question still lingers:why, in the majority with early cervical cancers no less, did the elderly makeso many seemingly negative treatment decisions when more effective, welltolerated alternatives existed?

Hysterectomy, including radical hysterectomy and pelvic lymphadenectomy,has been proven tolerable in all age groups (31,32). In the clinical setting of

early cervical cancer, where its cure-rates are at least equivalent to radiation,surgery offers important advantages including: shorter treatment time, accuratesurgical-pathologic staging furthering treatment to the specific patient, lesslong-term morbidity, better sexual function (33) (and yes, shocking as it isto generation X, us old people do have, and enjoy, sex too (16)). Nevertheless,in Wrights study, the early stage, older patients were three times more likelyto forego surgery and its benefits. Again, reasons from physiologic to psychosocialare likely (34). But, could some portion reflect a pessimistic, passhexperience when the surgical option was indeed less tenable in that age range;or worse, could it be a narrow one-sided reaction to a mere chronologic (age)number (29)?


32/825

Despite its advantages, surgery is not always the best recommendation forpatients with early cervical cancer, of course (35). Future studies may somedayshow radiation with sensitizing chemotherapy is generally superior to surgery,even in this setting (36). In the fast world of exploding science, all cliniciansare obligated to stay-tuned for breaking insights, and this surely applies tosubspecialty oncologists at centers where relatively esoteric cancers are morefrequently seen thus they are appropriately sought-out for their academic andclinical expertise (11). However the dynamic medical facts lay over time, twobroad concepts will likely remain constant. To the extent possible, the besttreatment of that moment is what should be employed for all patients (29).And, to meet this challenge, difficult as it is, health care must continue shakingingrained, out-dated perceptions such as radical pelvic surgery is too much forelderly patients to endure a standard teaching in Gynecologic Oncologyand Radiation Oncology fellowship programs not long ago. Fortunately realizationsabout this and similar matters are changing, to where the optimal use ofsurgery, radiation, chemotherapy, adjuvant treatments, etc., can occur into thetenth decade (3,9.37,38).

Maybe so, the skeptics respond, but the question of treatment-tolerance ismoot (18), since the elderly do intrinsically worse with cancer. Well admittedly,

with certain cancers, at certain ages, there is biologic-reality to this darktruism (39). Even assuming that the incomprehensible maze of confoundingvariables could somehow be perfectly controlled-for, there would still likely be oncologic-instances where older patients just fare fundamentally worse (4030).In fact, Wrights data supports this perception, though in reflection the authorsseem to question the conclusion. Then again, considering the physiology of aging,isnt this observation both logically inevitable, and yet, a false comparison(1)? The more relevant contrast would be between like-aged, older patientstreated differently (8). When up against younger, healthier counterparts, theolder group may inevitably have an inferior outcome; but there should also be

relative outcome-differences within the elderly cohort itself, according to theirtreatment (10). That benefit, mathematically smaller though it may be, is justas important humanistically as any other, especially to the patient and familyinvolved.

When available, biologic factors effecting oncologic-prognosis surely becomekey ingredients in the decision-making (4,38). At the same time, whileintegrating different sources of information into the equation, we must not fall prey to undue pessimism spinning from disorienting circular arguments (26). Inthe realm of potential reasons for the inferior oncologic-outcomes in the olderpopulation, it is the self-fulfilling prophecy that looms most ominous. Could a


33/825


subtle circular-fatalism be positively reinforcing an otherwise iffy proposition?To paraphrase an established therapeutic principle half treatments, wellintended as they are, rarely yield even half results. What then, do we expectto occur with "half" oncologic treatments, the types more typically receivedby older groups (8,37)? The virtues of extreme dose intensity notwithstanding,treatments administered to established therapeutic thresholds continue to carrythe best chance for a good outcome regardless of age (8). This is quality cancer care, the kind to be encouraged for its direct value to individuals, and its rippleeffects that, not unlike NASA, drive learning and progress for a wholly betterfuture.

While collectively championing the right of all patients to receive the besttreatment (25), what can we also do, personally, to improve the everyday? Manyideas, and hearts, will apply here. One is working to diminish any skewed age-oriented "medical thinking". Remembering the age-old principle, first thingsfirst is one practical, easy step, taken. In vitalizing the simple phrase into theformulation of real-life patient-centered recommendations, our best first-question

would seem: what is the optimal treatment for this (oncologic, cardiac,GI, etc) problem? With that universal answer in mind, secondary questions,like those relating to a specific patients physiologic risk factors, take theirplace in sequence to create the appropriate, patient-specific context for the finalconclusion. Could a minor change in the order of deductive questions, or in thejuxtaposition of age within medical case presentations, actually reduce bias-related blind spots to therapeutic choices? Wellokay, the syntax-thing maybe pushing it a bit, or even sillythen again, are we so sureand either way,what is the downside risk of trying? But, whats actually most important, isour simply thinking about these matters, and realizing that without fanfare, the seemingly little things within our control, add up and make a big difference.

As much as it does upon new technologies and new understandings oftenabout old ideas genuinely better health care depends on us for this vital,incremental change. The defrocked arbitrary mantra too old for the besttreatments after that certain age is an example of just such old thinking now thankfully at rest for lack of a priori foundation.


34/825

Snakes, Bugs & Us

Why do we do what we dooooostars in the sky, more than a few.Logic, science, proofs in season,mostly though others the actual reasons.Encouraged today to quietly think,of why we doo and possible links.Snakes and bugs here said to bemuch like us (you) but surely not me.For I am human, elite and evolved,in charge of the issues each easily solved.And too my choices, well those Im seeing,dont ask of the others affecting my being.Mysterious instincts, inkling, genes,intuitions contribute, but what does this mean?To knowledge amazing built by mankind,to vaccines and astronauts born of our minds.Intelligence vital, impressive for sure,but also explaining why humans are bores.More than blind to matters of fun,are we fooling ourselves on what makes us run?Biology, hormones, stealth pheromones make

all creatures in common thus you like a snake.Or is it bug-like, fall/summer nights same,dancing, no choice has drawn to the flame.Scaly reptiles, with scary, forked-tongues,scientists, doctors all suddenly one.Each on their journey cross unchosen rhymes,few concrete answers at just the right time.Okay ... grand drama, hyperbole here,but differences major would also seem clear.For humans have free-will their choices can makeless bothered by vagueness propelling the snake.

How sorry the species that knows not its roleworse yet to imagine a lack of control.But ask not the end of my why-do-I stew ?or through me to others in that that I do.Id rather seem certainlet mighty me reign Bravado lifes opera heir surgeon still feigned.Less lofty, such reasons in public, my fameI wonder if others would cause me shame?My wishful eyes see me not easily ruled,pray others not witness an obvious fool.But what purpose crude questions which push to thebrinksuggesting a kindred or possible link.

Exploring for common what good could then come,from seeing us similar under one sun?Or could being aware of more things that affectbring humbling insight, best choices expect.Thus rather than fearsome could forked-tongues beseenas searching for answers about what life means.Each probing forked-tongue just trying to learn,what this world is and which way to turn.Armed with kind-knowledge, Isaac Newton august,


35/825

still mysterious forces link snakes, bugs, and us.With fear, inch inch forward, dark skies should notbar,good service to others as metaphor stars.Incomplete answers, the most we can know,yet stars out this night, so each must still go.For what now is here, over that which seems not,for what now is clear and that which weve got.For each need, all creatures, so real on this dayin darkness, few answers forked-tongue show theway.Then as to the question, why do we dooooo ...stars in the sky, choices known left to you.

C. O. Granai, MD 12/13/2000Copyright 2000 by Womens OncologyAll Rights of reproduction in any form reserved.


36/825


References

What Matters Matter:

1.Crease RP. The most beautiful experiment. Physics World 2002;15:9:2.2.Rossouw JL, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Riskand benefits of estrogen plus progestin in healthy postmenopausal women: principal resultsfrom the Womens Health Initiative randomized controlled trial. JAMA 2002;288:321-333.3.Watson JD, Crick FHC. Molecular structure of nucleic acids A structure for deoxyribosenucleic acid. Nature 1953;171:737-738.4.Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the

human genome. Science 2001Human Genome Special Issue; 291:1304-1351.5.Oberlander J. The US health care system: On a road to nowhere? CMAJ 2002;167:163-8.6.Duff S. The best things in life are free; 2 Vermont hospitals abandon JCAHO accreditation.Modern Healthcare 2002;32(33):20-1.7.Cervantes Saavedra, Miguel de. The History of that Ingenious Gentleman, Don Quijote de laMancha (translated from the Spanish by Burton Raffell). New York: Norton, 1995.8.

Hippocrates. The genuine works of Hippocrates; trans. from the Greek, by Francis Adams.Baltimore: Williams and Wilkins, 1939.9.James B. Making it easy to do it right. N Engl J Med 2001;345(13):965-70.10.Osler W. Aequanimitas and other papers that have stood the test of time with anintroductionby Paul Dudley White. New York: Norton, 1963.11.Hundert EM. A Golden Rule: Remember the Gift. JAMA 2001;286(6):648-50.12.Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment preference

s of seriouslyill patients. N Engl J Med 2002;346:1061-6.13.Peipert JF. The economic value of medical research: Is it worth the investment?Obstet Gynecol2002;99:835-840.14.Grimes D. The CONSORT guidelines for randomized controlled trials in Obstetrics &Gynecology. Obstet Gynecol 2002;100(4):631-2.15.


37/825

Frankel F, Malin D, Shuett L. Scientific Photography from Talk of the Nation. National PublicRadio, September 27, 2002. Available at: http://search.npr.org/cf/cmn/segment_display.cfm?segID=15068616.Neuwirth ZE. Reclaiming the lost meanings of medicine. Medical Journal of Australia2002;176(2):77-79.17.HIPAA (Health Insurance Portability and Accountability Act). For detailed information, visittheir website at www.hipaa.org.18.Physician Behavior Policy. (Pamphlet and Mousepad) Medical Staff Services, COROBuilding,Room 190, 167 Point Street, Providence, RI 02903.19.Cohen JJ, Gabriel LA. Not just another business: Medicines struggle to preserve professionalismin a commercialized world. Obstet Gynecol 2002;100:168-9.20.The Advisory Board Company. The new economics of cancer care. Washington: Oncology

Roundtable, 2000.21.Donovan KA, Greene PG, Shuster JL, Partridge EE, Tucker DC. Treatment preferences inrecurrent ovarian cancer. Gynecologic Oncology 2002;86:200-211.22.Granai C: "Snakes, Bugs, and Us." SGO Issues (The Editor's Corner) vol. 20 no. 3: Society ofGynecologic Oncologists, 2001.23.Varnadoe K. Entering the software century. Art News 1992;91:57.


38/825

That Certain Age

1.Too old to care? Penson RT, Daniels KJ, Lynch TJ Jr. Oncologist. 2004;9(3):343-52.2.Geriatric oncology: challenges for the new century. Balducci, L. Eur J Cancer. 2000Sep;36(14):1741-54/3.You may think Im old, but cant you treat my cancer? DiSilvestro PA, Granai CO, GajewskiWH, Falkenberry SS. RI Med. 1995 May;78(5):143-4.4.Quality of life in elderly cancer patients. Repetto L, Ausili-Cefraro G, Gallo C, Rossi A,Manzione L.Oncol. 2001;12 Suppl 3:S49-52.5.Care of breast cancer in elderly women what does comprehensive geriatric assessment(CGA) help? Wedding U, Hoffken K. Support Care Cancer. 2003 Dec;11(12):769-74.6.

Physician-older patient communication about cancer. Greene MG, Adelman RD. Patient EducCouns. 2003 May;50(1):55-60/7.Perioperative risk assessment in elderly and high-risk patients. Richardson JD,Cocanour CS,Kern JA, Garrison RN, Kirton OC, Cofer JB, Spain DA, Thomason MH. J Am Coll Surg. 2004Jul;199(1):133-46.8.Physiological aspects of aging. Implications for the treatment of cancer. Lichtman, SM. DrugsAging. 1995 Sep;7(3):212-25.

9.Pharmacology of Chemotherapy in the older cancer patient. Balducci L, Beghr C. CancerControl. 1999 Oct;6(5):466-470.10.Treatment of cancer in old age, shortcomings and challenges. Wymenga AN, SlaetsJP, SleijferDT. Neth J Med. 2001 Nov;59(5):259-66.11.You're never too old. Surgery on patients of 80, 90, and up? It's gaining acceptance. ComarowA. US News World Rep. 2004 Jul 12;137(1):83-4, 87-8.12.

Cancer treatment and age: patient perspectives. Newcome PA, Carbone PP. J Natl Cancer Inst.1993 Oct 6;85(19):1580-4.13.Cancer control and the older person. Psychosocial issues. Vachon ML, Robinovitch A, BurlowJ, Ganz P, Hermann J, Joseph R, Kane RA. Cancer. 1991 Dec 1;68(11 Suppl):2534-9. 14.Comprehensive assessment of the elderly cancer patient: the feasibility of self-


39/825

report methodology.Ingram SS, Seo PH, Martell RE, Clipp EC, Doyle ME, Montana GS, Cohen HJ. J ClinOncol. 2002 Feb 1;20(3):770-5.15.Studies of comprehensive geriatric assessment in patients with cancer. Extermann M. CancerControl. 2003 Nov-Dec;10(6):463-8.16.Sexuality and sexual capacities of elderly people. Drench ME, Losee RH. RehabilNurs. 1996May-Jun;21(3):118-23.17.The frailty syndrome: a critical issue in geriatric oncology. Ferrucci L, Guralnik JM, CavazziniC, Bandinelli S, Lauretani F, Bartali B, Repetto L, Longo DL. Crit Rev Oncol Hematol. 2003May;46(2):127-37.18.Cancer chemotherapy in older adults. A tolerability perspective. Kimmick GG, Fleming R,Muss HB, Balducci L. Drugs Aging. 1997 Jen;10(1):34-49.19.Age as a bias for healthcare rationing. Arguments against ageism. Scharf S, Flamer H,

Christophidis N. Drugs Aging. 1996;9(6):399-402.20.Should the elderly receive chemotherapy for node-negative breast cancer? A cost-effectivenessanalysis examining total and active life-expectancy outcomes. Desch CE, HillnerBE, SmithTJ, Retchin SM. J Clin Oncol. 1993 Apr;11(4):777-82.21.Ageism and the abuse of older people in health and social care. Ward D. Br J Nurs. 2000 May11-24;9(9):560-3.22.Increasing aggressiveness of cancer care near the end of life. Is it a quality c

are issue? EarleCC, Neville BA, Landrum MB, Ayanian JZ, Block SD, Weeks JC. Am J Oncol Rev. 2004 July3;7:401-404.


40/825


23.Geriatric oncology. Medical and psychosocial perspectives. Wells NL, Balducci L. CancerPract. 1997 Mar-Apr;5(2):87-91.24.Psychosocial aspects of cancer in the elderly. Walker LG, Kohler CR, Heys SD, Eremin O. EurJ Surg Oncol. 1998 Oct;24(5):375-8.25.Cancer in America, 2004. Bosserman LD, Henderson IC. Comm Oncol 2004;1:30-35.26.Cancer screening in elderly patients: a framework for individualized decision making. WalterLC, Covinski KE. JAMA. 2001 Jun 6;285(21):2750-6.27.The outcomes and costs of acute myeloid leukemia among the elderly. Mensin J, Lang K, EarleCC. Arch Intern Med. 2002 Jul 22;162(14):1597-603.28.Older age underwriting: frisky vs frail. Bennett AK. J Insur Med. 2004;36(1):74-83.

29.Variations in the use of chemotherapy for elderly patients with advanced ovarian cancer:a population-based study. Sundarajan V, Hershman D, Grann VR. J Clin Oncol. 2002 Jan1;20(1):173-8.30.Psychosocial issues. Psychological and social issues for older people with cancer. Kane RA.Cancer. 1991 Dec 1;68(11 Suppl):2514-8.31.Radical hysterectomy in the elderly patient: analysis of morbidity. Fuchtner C,Manetta A,

Walker JL. Am J Obstet Gynecol. 1992 Feb;166(2):593-7.32.Radical hysterectomy in patients 65 years of age and older. Levrant SG, Fruchter RG, MaimanM. Gynecol Oncol. 1994 May;53(2):208-11.33.Radical hysterectomy followed by tailored postoperative therapy in the treatment of stageIB2 cervical cancer: feasibility and indications for adjuvant therapy. YessaianA, Magistris A,Burger RA, Monk BJ. Gynecol Oncol. 2004 Jul;94(1):61-6.34.Psychosocial issues. Psychological and social issues for older people with cance

r. Kane RA.Cancer. 1991 Dec 1;68(11 Suppl):2514-8.35.Surgical-pathological predictors of disease-free survival and risk groupings for IB2 cervicalcancer: do the traditional models still apply? Kamelle SA, Ruteledge TL, Tillmanns TD, GouldNS, Cohn DE, Wright J, Herzog TJ, Rader JS, Gold MA, Johnson GA, Walker JL, Mannel RS,McMeekin DS. Gynecol Oncol. 2004 Aug;94(2):249-55.


41/825

36.FIGO Stage IB2 cervix cancer and putting all your eggs in one basket. Ackerman I. GynecolOncol. 2004 Aug;94(2):245-6.37.Breast cancer in older patients. Kimmick G, Muss HB. Semin Oncol. 2001 Apr;31(2):23448.38.Life expectancy, co morbidity and quality of life: the treatment equation in older cancer patientsRepetto L, Comandini D, Mammoloiti S. Crit Rev Oncol Hematol. 2001 Feb;37(2):147-52.39.FIGO stage, histology, histologic grade, age and race as prognostic factors in determiningsurvival for cancers of the female gynecological system: an analysis of 1973-87SEER cases ofcancers of the endometrium, cervix, ovary, vulva, and vagina. Kosary CL. Semin Surg Oncol.1994 Jan-Feb;10(1):31-46.40.Geriatric assessments it useful in the selection of elderly tumour patients fora difficulttherapy?Krege S, Friedrich C, Lummen G, Pientka L, Rubben H. Urologe A. 2004

Aug;43(8):922-9.* Permission granted by Lippincott, Williams & Wilkins: What matters matter? C.O. Granai, MDP values, H values, Leadership, and Us. Obstet Gynecol. 2003 Aug; 102(2):393-396 * Permission granted by John Wiley & Sons, Inc.: That Certain Age. C. O. Granai, MD, Cancer,2005 Jan 1;103(1):5-10.


42/825

Gamete cryopreservationOvarian freezing - are we progressing?What are the gaps?

María Sánchez

Hospital Universitario Doctor Peset, Valencia.e-mail: [email protected]

It is estimated that in 2010 one of every 250 youngster between 20 and 29 yearsof age will be a cancer survivor, due to two major causes; in first place, theincidence of cancer is growing; in second place, the therapies are improvingsurvival. As survival rates keep on improving, protection against iatrogenicsterility, caused by chemotherapy (ChT) and/or radiotherapy (RT) is becominga main concern in medical research (1). Premature ovarian failure (POF) is alikely long term consequence of ChT and RT, as gonads are particularly sensibleto them. Increasing doses of ChT agents causes progressive destruction ofoocytes and follicles, suggesting a direct relationship between doses and POF(2). The recent report of the first human live birth after cryopreserved ovarian tissue autotransplantation (3), has unlocked the debate about its indications,efficacy and ethical considerations (4,5). Additionally, it brings an openingto community about a subject so far almost restricted to research. Nowadays,

oncologycal patients themselves are searching for information concerning theirreproductive chances and their hormonal function. Once they or their parents

are informed, they usually demand these possibilities to become a reality. Itis our task to offer them, both, the information and the solutions. The solutionsfor their reproduction include immature oocyte retrieval, in vitro maturationof oocytes, oocyte vitrification, and embryo cryopreservation. For being ableto achieve both, reproduction and ovarian hormonal function, ovarian tissuecryopreservation seems the option; though this option is not free of risks, andautografting could be hampered by tumour cell contamination. Technologiesare being developed for detecting residual disease (6). At present time, embryo


43/825


cryopreservation is the only clinically well established option.

Medical advances during last decades bring us to the fact that medical successobtained with the resolution of cancer, at present must be accompaniedby the accomplishment of patient´s quality of life. In children, teenagers andyoung women this quality of life will probably include gonadal hormonalfunction and maternity safeguard. Poirot suggested in 2002 that ovarian tissuecryopreservation should be offered to these patients (7). The idea of ovariantransplantation is not new, the first report about this issue is more than a centuryold (8). Studies in small laboratory rodents have demonstrated that fertility canbe restored by transplanting whole cryopreserved ovaries (9), and also usingvascular anastomosis in dogs, sheep and rabbits (10, 11); but this ideal solutionis not feasible at this time in humans. Thus, transplantation of cryopreservedovarian tissue offers a means of preserving reproductive function. Provided theappropriate cryopreservant is used, primordial oocytes in ovarian tissue toleratefreezing/thawing surprisingly well. (Liu J, Van Der Elst J, Van der Broecke R,Early massive follicle loss and apoptosis in heterotopically grafted newborn

mouse ovarios. Hum Reprod 2002;17:605-611). The major problem affectingautograft success is the ischaemia reperfusion. Ovarian allografting requiresthe use of toxic drugs which preclude its clinical application; egg donation isa simpler and well established alternative.

We are cautiously progressing on ovarian freezing due to a certain extent tothe tremendous biological value of ovarian tissue samples which mess up withthe performance of long studies. The best way to try to answer these questionsis to present our work.

Initially, we experimented with two slow freezing protocols for ovariantissue as well as with vitrification of embryos at different stages. Viability of

ovarian tissue after thawing was also assessed.Then, we autotransplanted fresh left ovarian cortex orthotopically ontoright medulla after extracting whole right cortex, to twelve 39 -42 old agedwomen undergoing abdominal hysterectomy. Particular care was taken to avoidischemia and to remove all cortical tissue except the transplantated one. Therewas evidence of function of grafts. With different patterns, FSH levels showedovarian function in all twelve women and we were amazed to find ovulation(settled on vaginal ultrasound and progesterone serum levels) in ten patients.These studies established that the technique of surgical transplantation wastechnically feasible and ovarian function could be restored.

Recently, we have obtained the accreditation for the extraction and implant

of autologous ovarian tissue (Doctor Peset Universitary Hospital, Valencia Spain), in coordination with the creation of an ovarian tissue bank (Transfusion


44/825

Centre of Valencia Autonomic Community, Valencia Spain), within the PublicHealth System. This is a pioneer experience in our country, where only ourgroup is allowed to in Spain.

At the moment, besides managing the programme of extraction and implantof autologous ovarian tissue, we are performing xenotransplantation on malenude mouses. We subcutaneously insert pieces of ovarian cortex from fertileage donors on nude male mousses, and different experiments are carried out.

All these protocols and studies will be presented and discussed at COGI2005.

References

1.Blumemfeld Z, Avivi I, Ritter M, Rowe JM. Preservation of fertility and ovarianfunction andminimizing chemotherapy-induced gonadotoxicity in young women. J Soc Gynecol Investig1999;6:229-239.2.Clark ST, Radford JA, Crowther D, Swindell R, Shalet SM. Gonadal function follow

ing chemotherapyfor Hodgkin`s disease: a comparative study of MVPP and a seven drug hybridregimen. J Clin Oncol 1995;13:134-139.3.Donnez J, Dolmans MM. Livebirth after cryopreserved ovarian tissue autotransplantation.Lancet. 2004 Dec 11;364(9451):2092-3.4.Oktay K, Sonmezer M. Ovarian tissue banking for cancer patients: fertility preservation, notjust ovarian cryopreservation. Hum Reprod. 2004 Mar;19(3):477-80.5.Revel A, Schenker J. Ovarian tissue banking for cancer patients: is ovarian cort

ex cryopreservationpresently justified? Hum Reprod. 2004 Jan;19(1):14-9.6.Schröeder C.P et al. An in vitro model for purging of tumour cells from ovarian tissue. HumReprod 2004; 19:1069-1065.7.Poirot C, Vacher-Lavenu M-C, Helardot P, Guibert J, Brugières L, Jouannet P. Human ovariantissue cryopreservation: indications and feasibility. Hum Reprod 2002;17:1447-1452.8.R.T. Morris, The ovarian graft. N Y Med J. 1985;62:436.

9.Wang X et al. Fertility after intact ovary transplantation. Nature 2002;415:385. 10.W.J. Dempster. A technique for the study of the behaviour of the autotransplanted kidney,adrenal gland and ovary of the dog. J. Physiol. 1954;124:1516.11.J.R. Goding, J.A. McCracken and D.T. Baird, The study of ovarian function in the ewe by


45/825

means of a vascular autotransplantation technique. J. Endocrinol 1967;39:3752.


46/825


Transplantation of cryopreservedovarian tissue

Jacques Donnez, MD, PhD*, Marie-Madeleine Dolmans, MD,Dominique Demylle, BS, PhD

Gynecology Research Unit, Université Catholique de Louvain, Brussels, Belgium*Department of Gynecology, Cliniques Universitaires St. Luc, Université Catholique deLouvain, Avenue Hippocrate, 10, B-1200 Brussels BelgiumThe lifesaving treatment endured by cancer survivors provokes, in many cases,early menopause and subsequent infertility. In clinical situations where thereis often a pressing need to start chemotherapy, ovarian tissue cryopreservationlooks to be a promising option to restore fertility.

It has been estimated that, by 2010, one in 250 people in the adult populationwill actually be childhood cancer survivors [1].

The treatment of childhood malignancy is becoming increasingly effective.Aggressive chemotherapy and radiotherapy, as well as bone marrow transplantation,

can cure more than 90 percent of girls and young women affected by suchmalignancies. However, the ovaries are very sensitive to cytotoxic treatment,especially to alkylating agents and ionizing radiation, generally resulting in theloss of both endocrine and reproductive function [2]. Moreover, it is known that uterine irradiation at a young age reduces adult uterine volume [3].

There are several potential options available to preserve fertility in patientsfacing premature ovarian failure, including immature and mature oocytecryopreservation, embryo cryopreservation and cryopreservation of ovariantissue[4,5].

For those patients who require immediate chemotherapy, cryopreservationof ovarian tissue is a possible alternative [4,6,7].


47/825

History of experimental and clinical studies

To date, ovarian tissue has been successfully cryopreserved and transplanted inmice and rodents, as well as large animals like sheep and marmoset monkeys[8-10]. The first successful fertilization and pregnancy following egg collectionfrom fresh transplanted ovarian tissue in a primate was recently described [11]. The grafted tissue functioned without any surgical connection to major bloodvessels. Experimental studies have indicated that the decrease in the numberof primordial follicles in grafted tissue is due to hypoxia and the delay before reimplanted cortical tissue becomes revascularized. The loss of primordial folliclesin cryopreserved ovarian tissue after transplantation is estimated to be 50to 65 percent in some experimental studies [7,8,12]. In one experimental study,in which ovarian

controversies in o&b and infertility (athens 14-17 april 2005)

Documents