Newsletter13

Spring 2010

Advances and challenges in PKU (2nd European Phenylketonuria Group (EPG) Symposium)

ART: experimental bases for improving outcomes for the benefit of patients

Optimizing MS therapy - current treatment models and future options

Five questions to Pramuan Virutamasen

Five questions to Pedro Barri

Forthcoming meetings

Advances and challenges in PKU (2nd European Phenylketonuria Group (EPG) Symposium)

Munich, Germany; January 22-23, 2010

The introduction of pharmacological treatment will profoundly change the approach to phenylketonuria (PKU). This take-home message emerged during the second meeting of the European Phenylketonuria Group (EPG) Symposium ‘Advances and challenges in PKU’ held in Munich, 22-23 January. The burden of lack of adherence to diet on PKU management remains significant, despite the relevant improvement of dietary strategies. Moreover drop out from diet means, for many subjects, drop out from follow-up. As a consequence, many PKU patients skip the assessment of the laboratory parameters and clinical and sub-clinical manifestation of the disease that are crucial to monitor its evolution over time. In many patients the drug, well integrated in the treatment protocol, allows the introduction of less restrictive diets, thus improving quality of life of PKU patients and increasing long-term adherence to therapy. These new approaches were emphasized by the speakers and also by the participants. Participant viewpoints collected during the workshops by a voting system were in full agreement with these new perspective. Six workshops were dedicated to the main practical issues of PKU patients’ management and allowed participants to interact with renowned experts in the field. There was particular interest in the workshops dedicated to the integrated management of the disease and quality-of-life assessment. The three lectures that preceded the Workshop session were exhaustive reviews of relevant aspects of present and future PKU management. The first one, delivered by Nicola Longo (USA) showed how PKU management will evolve, in the future, towards enzyme substitution therapy with pegylated phenylalanine ammonia lyase, and Steven Dobrowolski (USA) reported intriguing aspects of the relationship between genetic background and disease manifestations. Finally, Ania Muntau (Germany) discussed one of the hottest topics related to the introduction of drug treatment: the assessment of responsiveness.

Three outstanding lectures opened the second day of the conference. Roland Kreis, (Switzerland) addressed the role of Magnetic Resonance Spectroscopy in monitoring brain phenylalanine concentration and transport dynamics at the blood/brain barrier. Alberto Burlina (Italy) started with the differential diagnosis of tetrahydrobiopterin cofactor deficiencies and then considered the therapeutic approaches. Provocative, as usual, Francjan Van Spronsen (The Netherlands) dealt with the management of mild hyperphenylalaninemia, addressing all the most debated aspects in this field.

The Conference included not only invited lectures, but also oral communications and a poster session based on submitted abstracts. The session dedicated to the oral communications covered a wide range of topics, from basic research findings to practical aspects of clinical management. Serono Symposia International Foundation rewarded the two best oral communications selected by the Scientific Committee of the Symposium. The two winners were Michael Staudigl (Germany) and Margreet van Rijn (The Netherlands) who delivered the following oral communications, respectively: 'Direct in-well activity measurement of phenylalanine hydroxylase reveals positive cooperativity for the binding of BH4' and 'Cost and availability of special dietary products for PKU in Europe'.

To underline how dramatic the changes in PKU management have been in recent years, a 'Meet the pioneers' session was included in the afternoon of the second day of the Conference. It offered a lively story of the evolution of knowledge about PKU and showed that most of the men and women who influenced the history of this disease were not only excellent scientists and clinicians, but also people with deeply felt humanity. The Symposium closed with an elegant keynote lecture by Charles Scriver (Canada) who received the 2010 Folling Award. A very stimulating comment was made during the meeting by Milan Blaskovics (USA), one of the 'Pioneers': 'finally I realized what this Conference is, the Conference of the International Society of PKU. Something which didn’t exist before and now offers a unique opportunity of gathering together healthcare professionals interested in this disease'.

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ART: experimental bases for improving outcomes for the benefit of patients

Istanbul, Turkey; February 19-20, 2010

Closing the gap between the most recent research findings and the clinical practice of ART was the challenging objective set for the 2010 Annual Meeting in reproductive medicine, held in Istanbul. A group of outstanding scientists, some of them rarely invited to events held in Europe, gathered to achieve this objective. Each session featured a ‘symposium-within-the-symposium’ format where a specific aspect of ART was addressed in depth.

Session I refreshed participants’ knowledge of the physiology of reproductive function, according to some intriguing recent advances in the understanding of physiologic mechanisms. Claus Yding Andersen (DK) focused his first lecture on the function of anti-Müllerian hormone (AMH) in the ovary which, he claimed, is not fully understood, but about which much intriguing evidence has recently been collected. In particular he reported results of his group’s studies on follicular fluid hormones trends and corresponding gene expression profiles of granulosa cells. The objective of Mario Ascoli’s (USA) presentation was to explore why luteinizing hormone (LH) and follicle stimulating hormone (FSH) have different effects on the ovary, despite the similarity of the two gonadotrophins and their receptors. He reported evidence of the hypothesis that LH and FSH activate the same signalling pathways, but their final effects depend on receptor density. Remi Dumollard (F) delivered an interesting lecture on embryo physiology and metabolic functions, stressing in particular the latter, and suggesting that the evaluation of the embryo’s metabolism will be increasingly relevant to assess its quality. After a second talk by Claus Yding Andersen, dedicated to the issue of sensitivity of the pool of small antral follicles to FSH prior to stimulation, Aydin Arici (USA) provided participants with a comprehensive review of evidence available on the relationships between gene expression and endometrial changes aimed to implantation. In particular he explained how HOXA10 expression, in the human endometrium, is under the influence of steroid hormones, and is up-regulated during the implantation window. Antonis Makrigiannakis (GR) dealt with the challenging topic of immune mechanisms activated in the embryo invasion phase and explained how the study of pathological implantation has aided our understanding of normal, healthy implantation.

With so many new insights in reproductive function physiology, may we now say something new about the effects of ovarian stimulation on those mechanisms? In Session II, Marie Louise Grondal (DK), Samir Hamamah (F) and José Horcajadas (SP) addressed this question. The first speaker focused on the transcriptome of human granulosa cells in ART. In particular, she showed how LH receptor expression and genes involved in cholesterol and steroid biosynthesis vary in hMG-treated compared with r-hFSH-treated women’ granulosa cells. Samir Hamamah reported the results of his group’s experiences on the evaluation of cumulus cells, using a genomic test (‘G-test’), to assess the potential of the embryo to implant and develop. He also described studies investigating LH/hCG receptor expression in cumulus cells in patients undergoing ovarian stimulation. José Horcajadas closed the session addressing the gene expression analysis of endometrial cells, during the implantation window, both in natural and stimulated cycles and the impact of ovarian stimulation protocols on endometrial development.

Session III was dedicated to the more advanced methods of screening embryo characteristics and predicting cycle outcomes. Emre Seli (USA) delivered the first of his two outstanding lectures reporting some results from his research group on metabolomics. Excellent talks were also given by William Kearns (USA), another renowned scientist, and Tamara Garrido (SP). The latter, a young researcher at the IVI Foundation in Spain, delivered an interesting lecture on research methods and outcomes on embryo proteomics and secretomics. This session provided participants with a comprehensive overview of advances in pre-gestational diagnosis and showed a trend towards increase of result robustness and decrease of risks. Robert Fischer (G) and Hakan Yarali (TR) were very successful in stimulating discussion during the following panel session which tried to put into perspective how these methodologies might be implemented in clinical practice.

The last Session of the meeting was aimed at delivering take-home messages that participants could apply in aspects of their daily practice. Carlo Alviggi (I) opened with an elegant lecture on ovarian stimulation which provided participants with some intriguing explanations of clinical trial results that seem contradictory, but can be explained by referring to specific physiologic mechanisms. In particular, he discussed the concept of ovarian resistance to r-hFSH. On the basis of the current literature, he claimed that it is possible to argue that hypo-response is related to specific gene polymorphisms. More specifically, it has been found that ovarian resistance is associated with a common LH polymorphism that encodes a protein with altered activity and he suggested that, if endogenous LH activity is inadequate, supraphysiological levels of FSH may be needed to compensate. Marc-André Sirard (CAN) and Emre Seli (USA) addressed the very hot topics of, respectively, oocyte and embryo selection and showed how some of the advanced methods reported in the previous sessions have already provided, or are about to provide, clinicians with new tools that could be extremely effective in improving outcomes. Finally, Nick Macklon delivered an excellent talk where the ‘black box’ of implantation was presented as an increasingly clear aspect of assisted reproduction techniques. He claimed that pre-implantation loss is estimated to be approximately 30%, went on to discuss the limitations of current approaches to assess endometrial receptivity before reviewing the available data to support adjunctive therapies, including aspirin and glucocorticoids, for improving endometrial receptivity. He suggested that, although the data were largely negative, there may be some benefit in certain patient groups.

The success of the meeting confirmed that doctors involved in assisted reproduction in daily practice are very interested in acquiring detailed updates on physiology and pathophysiology of reproductive function, genetics and metabolomics where they can find explanations of successes and failures of their procedures and ideas to improve outcomes. But the challenge to close the gap between the research findings and the clinical practice has been won because speakers were able to ‘translate’ extremely complex knowledge into information that the audience would find directly useful.

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Optimizing MS therapy - current treatment models and future options

Rome, Italy; March 12-13, 2010

For decades the main objectives of multiple sclerosis treatment have been to reduce disease activity and slow its progression. The drugs that will be introduced in next years will change the focus of multiple sclerosis management, shifting attention to goals such as the disease activity free status and the disability progression stop. These were the key take-home messages delivered at the Serono Symposia International Foundation Annual Meeting in Multiple Sclerosis. The program was designed to guide participants in this leap towards the future of multiple sclerosis management.

The first Session provided an overview of topics that were to be addressed in depth in the following part of the meeting. Patrick Vermersch (F) highlighted that the alternative to the usual escalating therapy is an induction therapy that provides a more ‘aggressive’ approach, aimed to tackle inflammatory mechanisms in the early phases of multiple sclerosis, when they are more active. Jerry Wolinsky (USA) gave an overview of efficacy and safety of the upcoming drugs, concluding that ‘as effect sizes have grown, so have potential risks‘ meaning that their administration should be carefully evaluated in terms of efficacy/safety balance.

The rationale and objectives of the disease activity free goal in multiple sclerosis was introduced in Session II in an outstanding lecture by Fred Lublin (USA). He explained that this goal had been considered in the past, but it was only recently that the outcomes of clinical trials of new drugs had suggested the possibility of achieving the goal in a substantial percentage of patients. He proposed criteria aimed to define the disease activity free status, some of them still being under discussion, and discussed evidence, collected in clinical trials that showed the percentage of patients that reached this goal. He also stressed that there is a relevant difference between say disease free status and disease activity free status, and stressed that now only the latter goal is reachable. Eva Havrdová (CZ) and Ludwig Kappos (CH) focused their talks on two approaches possibly aimed to reach main goals of multiple sclerosis treatment. In particular, the former speaker emphasized the risk of missing, in some patients, the most promising therapeutic window delaying the administration of more aggressive treatments. Ludwig Kappos depicted the complex pharmacological armamentarium that will become available for multiple sclerosis specialists in the near future and presented some add-on schemes that combine old and new compounds.

If aggressive treatment protocols are now available to achieve ambitious goals in some patients, how are suitable subjects to be selected? Mar Tintorè (S), Per Soelberg Sørensen (DK) and Giancarlo Comi (I) addressed this question in the third session. The first two speakers explained how multiple sclerosis progression could be predicted, respectively, in naive and treated patients, on what criteria this prediction should be based and how progression prediction should contribute in therapeutic choices. Giancarlo Comi indicated how treatment can be personalized, with a focus on a ‘selective induction’ approach for patients where multiple sclerosis shows an aggressive profile.

In Session IV, Bernd Kieseier (D) delivered a provocative talk on the escalating therapy. ‘Is it already time for a new way of thinking/treating?’ was one of the question the speaker answered, sharing published data and personal experience with the audience. Moreover, he highlighted that each step in escalating treatments must be weighted according to a careful evaluation of the risk/benefit balance and that, in some subjects, first line drugs should be selected with a view to future escalation of treatment potency. Bone marrow transplantation can be considered as the last step of an escalating approach, with the aim of resetting the immune system. Giovanni Luigi Mancardi (I) gave an overview of the state of the art of this therapy in multiple sclerosis.

Session V was dedicated to primary progressive multiple sclerosis (PPMS) and Alan Thompson (UK) dealt with the challenging topic of predicting disease progression in this severe form of the disease. Studies on the natural history of PPMS provided new insights in disease pathology and course, and indicated that some of its characteristics adversely influence the progression, such as a shorter time to reach EDSS 3 and the evidence of three or more neurological systems affected by the disease at onset. Clinical trials performed in PPMS often have poor outcomes, but the evidence collected contributed to increasing the knowledge of PPMS. Douglas S Goodin (USA) provided a comprehensive review of clinical trials outcomes in PPMS and concluded that, even if no therapeutic approach has been demonstrated to alter definitively the course of PPMS, improvements in research methodology and patient selection may help to achieve better results.

Discussion of case studies animated Session VI where David Bates (UK), Carlo Pozzilli (I) and Mar Tintorè shared three challenging cases with the audience: treatment initiation in Clinically Isolated Syndrome (CIS), therapy switch after failure of a first-line treatment and management of an aggressive form of relapsing remitting multiple sclerosis. Participants were asked to provide their opinions on different management options using an interactive voting system and the outcomes stimulated much discussion.

Overall, the meeting was characterized by a lively interaction between faculty and audience. The availability of the voting system was helpful in stimulating interaction in all the sessions, but the enthusiastic dedication of David Bates, the Scientific Organizer of the meeting, in chairing sessions and stimulating discussion was crucial.

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Five questions to Pramuan Virutamasen

From ovarian stimulation to the laboratory: is there room for improvement?
Pre-ASPIRE meeting, Bangkok

Professor Emeritus Pramuan Virutamasen is the Scientific Organizer of the pre-ASPIRE meeting 'From ovarian stimulation to the laboratory: is there room for improvement?'. The meeting is targeted at clinicians and scientists working on assisted reproduction techniques and will cover new achievements in reproductive function physiology, recent achievements in endometrial function in stimulated cycles and new approaches to personalizing IVF

We asked Professor Virutamasen five questions to put the meeting in context

Who are you?
I am Professor Emeritus Pramuan Virutamasen, Department of Obstetrics and Gynaecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

What are your main fields of interest within assisted reproduction?
My main area of interest is reproductive endocrinology relating to oocyte and embryo development and embryonic stem cell.

Which Asian countries are most advanced in research in assisted reproduction techniques, and which are the topics of greatest interest?
As far as I know, Singapore, Taiwan, Japan, China and South Korea are the countries with the most advanced research in ART. They are researching in-depth into assessment of oocyte and embryo and uterine receptivity for implantation.

Where in Asia do you expect there to be growth in centers dedicated to infertility treatment and what do you think will be the reasons for the growth?
China, Vietnam, South Korea and Thailand are countries with the greatest growth in centers dedicated to infertility treatment. Cultural reasons, infertility improvement and declining birth rates are the main reasons for this growth.

What are the major challenges in the medical education of healthcare professionals dedicated to infertility treatment?
The key criteria for success in the treatment of infertile couples are the skills of well-trained embryologists and clinicians, including nurses. Continuing training and development of healthcare professionals concerned in every aspect of the medical ART are the major challenges to maximize the optimum outcome.

More information about 'From ovarian stimulation to the laboratory: is there room for improvement?'

Five questions to Pedro Barri

Challenging issues in ART

The congress Challenging issues in ART will bring together many clinicians in the fertility field in Barcelona, Spain, in November this year. We asked Professor Pedro Barri, the Scientific Organizer of this meeting, five questions to find out more about the objectives of this meeting.

Who are you?
I am the Director for the Department of Obstetrics, Gynecology and Reproduction of the USP Institut Universitari Dexeus, Barcelona (Spain)

Prof. Barri can you describe your department and your current field of scientific researches in infertility?
Our Department was created in 1937 and in 1989 the Spanish Ministry of Health granted us the status of 'Teaching hospital' for the national medical residents' qualification. The Autonomous University of Barcelona gave us the title of University Institute.

In 2009 our medical activity has been mainly focused on the following topics:
    104.000 outpatient consultations
    2.700 obstetrical procedures
    2.100 gynecologycal operations
    1.800 IVF cycles

Our main scientific interests are:
    Endometriosis-associated infertility
    Implantation failure
    Bad response to ovarian stimulation
    Patient drop-out

You are the Scientific Organizer of the Symposium 'Challenging issues in ART': what is the target audience for this meeting?
The conference target audience is clinicians and scientist interested in infertility, and lectures within this event will be made by high-level experts in the specific clinical field.

The continuous advances in ART procedures now make it possible to implement some of them in subjects where infertility is combined with other disorders and diseases, what are the educational objectives that you set when you designed the program of this Symposium?
Yes, it is undoubtedly true that, over the last ten years, successes in ART procedures have dramatically increased, which has provided the opportunity for extension to subjects where the reproductive function is highly threatened. The aim of this congress is therefore to review and analyze all the potential challenging situations in patients undergoing assisted reproduction techniques. The program will pay particular attention to the current practical approaches in the management of those cases, such as patients with genetic or systemic diseases, patients with poor ART outcomes, patients with surgical issues or with disabilities, cancer treatments survivors, etc, where the normal procedures might result in reproduction failure. This should allow all attendees to bring back home a better clinical approach of challenging ART patients.

More information about 'Challenging issues in ART'

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