WHO and six publishers launch Access to Research, internet initiative for developing countries

Health-related professionals in ~70 developing countries have gained free access, through the internet, to one of the world’s largest collections of biomedical literature. They will benefit from an initiative launched by the World Health Organization and six medical journal publishers, which WHO Director-General Dr Gro Harlem Brundtland has described as "perhaps the biggest step ever taken towards reducing the health information gap between rich and poor countries". The Access to Research initiative enables accredited universities, medical schools, research centers and other public institutions in developing countries to gain access to the wealth of scientific information contained in >1000 different biomedical journals produced by these publishers. Until now, subscriptions to these journals, both electronic and print, have been priced uniformly for such institutions, irrespective of geographical location. Many key titles cost more than US$1500 per year, and the average subscription costs several hundred dollars, putting the journals beyond the reach of a large majority of health and research institutions in the poorest countries. Last year WHO, working with the BMJ, approached six medical journal publishers: Blackwell, Elsevier Science, the Harcourt Worldwide STM Group, Wolters Kluwer International Health & Science, Springer Verlag and John Wiley. The aim was to bring them together with the countries concerned to seek a more affordable pricing structure for online access to their international biomedical journals.

The first stage of the initiative will make >1000 of their journals available free to institutions in those countries that are eligible. This availability began with the opening of the Health InterNetwork website: www.healthinternetwork.net A second stage will involve similar access at significantly reduced prices for institutions in a second, smaller group of more developed countries. WHO and the publishers will work with the Open Society Institute of the Soros Foundation Network and other public and private partners to extend the initiative; for example, through training for research staff, and improving internet connectivity. The Access to Research initiative is expected to last for at least 3 years, while being monitored for progress. Decisions about how to proceed with further developments will grow from the precedent it sets, and will be informed by the working relationships which have evolved among the publishers and participating institutions. The initiative itself is a major aspect of the work of the Health InterNetwork project which was introduced by United Nations’ Secretary-General Kofi Annan at the UN Millennium Summit in the year 2000. Led by WHO, the Health InterNetwork aims to strengthen public health services by providing public health workers, researchers and policy makers with access to high-quality, relevant and timely health information through an internet portal. It further aims to improve communication and networking. As key components, the project will provide training as well as information and communication technology applications for public health. The project is led by Dr Michael Scholtz, Special Representative of the WHO Director-General. He stated: "This launch sees the beginning of a new way to bridge the digital divide in health, and an important move by the publishers in facilitating the flow of health information using the Internet."

Paul Carbone dies from a heart attack in Singapore

Paul P. Carbone, MD, former director of the University of Wisconsin Comprehensive Cancer Center, former ASCO and AACR President, friend and past mentor of numerous members of ESMO, including some representatives of the Executive, died unexpectedly on Friday 22 February 2002 in Singapore of an apparent heart attack. Carbone, aged 70, had been in Singapore since December 2001, where he had been asked by the National University of Singapore to assist in the development of a comprehensive cancer program. Paul Carbone had served at the National Cancer Institute as Associate Director of Medical Oncology from 1960 until 1976, from where he went to the University of Wisconsin-Madison in 1976. One of the ‘founding fathers’ of ASCO, Paul Carbone said: "ASCO’s initial gathering, held during the 1965 American Association of Cancer Research (AACR) conference, drew 65 attendees. We met in a single room; about 65 of us could all get together. It was then very difficult to present papers at the American Society of Hematology—they weren’t really interested in cancer papers—and hard for a clinical researcher to become an AACR member. That was the genesis of ASCO."

An activist against the tobacco industry, he helped establish the local Tobacco Coalition, as well as the Madison Center for Tobacco Research. On a more human note one can read in the University of Wisconsin news that John Niederhuber, MD, Director of the UW Comprehensive Cancer Center said: "Above all else Paul Carbone was the ultimate husband, father and grandfather. In his long and distinguished career as UWCCC Director and Chairman of the Eastern Cooperative Oncology Group, he touched the lives of many students, faculty colleagues and patients—not only here at the University of Wisconsin but around the world."

Tom Connors, a giant of European oncology, passes away

Professor Thomas A. Connors, whom many of us knew as Tom, died on the morning of 4 February 2002, losing his personal fight against cancer. He was Director of the Medical Research Council Toxicology Unit, Carshalton, London, from 1976 until his official retirement in 1991. Herbie Newell reminds us that Tom contributed greatly to the studies of oxazaphosphorine metabolism that identified the importance of cytochrome P450-mediated activation pathways to the antitumor activity and urothelial toxicity of this class of drugs—to this day, a textbook example. His group performed key preclinical experiments with cisplatin, and, along with Ken Harrap and Hilary Calvert, he identified carboplatin. He pioneered in the area of antibody and gene directed enzyme prodrug therapy, as well as polymer therapeutics, and a large number of clinical trials have stemmed from this work. Tom and Brian Fox established the CRC Phase I/II Clinical Trials Committee in 1980. It is thanks to Tom Connors that rodent-only toxicology was eventually included in European Medicines Evaluation Agency guidelines, an achievement of which he was justly proud. He was an active member of the European Organisation for Research and Treatment of Cancer (EORTC) for many years, being elected to the position of Chairman of the Laboratory Research Division in 1993, and a member of the EORTC Board from 1991 to 1996. We share the words of Herbie Newell: "As a character who was larger than life, Tom’s contribution will outlive him in many ways."

Children and drugs (no, not those they are ‘offered’ outside school, or even inside...)

A new legislation, called the Best Pharmaceuticals for Children Act that went into effect in January 2002 in the USA made a matter of public law the existence of the US Food and Drug Administration (FDA) Pediatric Oncology Advisory Subcommittee. The Pediatric Oncology Advisory Subcommittee last met on 12 March 2002. The agenda initially included three subjects to be discussed; conflict of interest with regard to investigators having potentially conflicting roles in the conduct of studies, off-protocol access to investigational medications, and access to investigational agents for non-clinical studies. There were to be representatives of about half a dozen major, and some smaller and mid-sized, pharmaceutical companies on the panel and making presentations, as well as patient parents, academic investigators and, USA and foreign regulators. The subsequent meeting was planned for the end of June 2002. The two subjects were to be the monitoring of studies (what type, how often, the use of Data Monitoring Committees and their possible role, etc.) and a broad discussion of the Best Pharmaceuticals for Children Act. But this was without anticipating a lawsuit...

As stated by Lisa Richwine from Reuters: "Studying medicines in children had been a neglected area of medical research, leaving doctors guessing which medicines and what doses were safe for them. The FDA pediatric rule, put in place in 1998, mandated that drug companies study how new medicines affect children, except when the FDA grants waivers." One could comment that the Best Pharmaceuticals for Children Act was a consequence of this rule.

Two ‘free-market advocacy groups’ and a physicians organization had challenged the rule in a December 2000 lawsuit. In response to this lawsuit challenging its authority to impose such requirements, which were also opposed by drugmakers, the FDA said, on 18 March 2002, that it would put its ‘pediatric rule’ on hold for 2 years while it evaluated whether the recent legislation made the rule unnecessary. During that time, the FDA would study whether another measure, the pediatric exclusivity law signed in January 2002, made the rule unnecessary. This law provides an incentive to drug manufacturers who study products in children. Each medicine studied can gain an extra 6 months without generic competition, time that can mean hundreds of millions of dollars to drug companies.

The US Congressional Democrats immediately reacted and said that both the rule and the law were necessary to ensure drug companies research medicines important for children’s health. The rule gives the FDA power to require pediatric studies, while the exclusivity law is voluntary for pharmaceutical companies.

Regulations: difficulties with congress material...

Rules about material that can be put on display at different meetings vary from country to country. In Europe, national legislation still prevails, but for international meetings, such as ESMO, companies most often use information which reflects European Medicines Evaluation Agency (EMEA) acceptance of the product. In the US material containing ‘non-FDA’ approved data should be labeled "For foreign delegates only", but misunderstandings can occur. In July 2001, FDA Regulatory Review Officer Joseph A. Grillo, PharmD, wrote to Alan R. Bergstrom, Senior Manager, Regulatory Support, US Drug Regulatory Affairs & Compliance, Aventis Pharmaceuticals:

to notify Aventis Pharmaceuticals (Aventis) that the Division of Drug Marketing, Advertising and Communications (DDMAC) had identified promotional activities that were in violation of the Federal Food, Drug, and Cosmetic Act (Act) and its implementing regulations. Specifically, Aventis had promoted Taxotere for the (editors note: USA) unapproved use of first-line treatment of locally advanced or metastatic breast cancer at their commercial exhibit booth at the 37th American Society of Clinical Oncology (ASCO) Annual Meeting held in San Francisco, California in May 2001. In the commercial exhibit booth, Aventis disseminated a promotional brochure describing the safety or effectiveness of their drug Taxotere for the (editors note: USA) unapproved use of first-line treatment of locally advanced or metastatic breast cancer. This brochure was freely available to all attendees at the ASCO Annual Meeting and contained conclusionary statements such as: "Introducing A[driamycin] T[axotere]—the only taxane combination approved for the first-line treatment of locally advanced or metastatic breast cancer."

This information was obviously reflecting the European Commission decision of September 2000! Which granted an extension to the marketing authorization for Taxotere (docetaxel) in the 15 Member States of the European Union for the treatment, in combination with doxorubicin (Adriamycin), of patients with locally advanced or metastatic breast cancer who have not received previous cytotoxic therapy for this condition. This authorization followed the positive opinion by the Committee for Proprietary Medicinal Products, the scientific committee of the EMEA.

CME: an obligation, but what if...

What if governments, in their infinite wisdom, decide to decrease the ‘influence’ of pharmaceutical companies on medical congresses? One can read now in Italian newspapers (Corriere della Sera, 29 March 2002) and in German magazines (Focus, 9 March 2002), among others, that industry has exaggerated and many meetings are an extremely expensive promotion of a product. This is correct, but it is part of the freedom of information. Obviously, an unpleasant aspect is the often ‘touristic’ location of such meetings, which are, however, often determinants of the attendance... But the risk is that by wanting to put a halt to the wildest promotional behavior of some companies, governments will block those meetings which are truely of an educational nature, such as those organized by ESMO, ESO and other FECS associated entities, which rely on industry support, direct and indirect. As long as governments fail to realize the importance of transcultural meetings in the field of medicine, as long as they do not understand how important it is to see how colleagues work worldwide, one risks some unrealistic suggestions, like promoting the use of the internet for continuing medical education (CME), which is not yet better than reading excellent journals like Annals. CME is not only about learning the contents of a telephone book, it is about learning clinical skills, and for this the exchange of experiences gained by personal contact is of paramount importance. Our professional organizations should promote our CME work within the EU Commission, and with all governments, before legislation is passed which will allow only the richest doctors to go to international meetings.

Awards, appointments: Europeans honored by AACR and a European enters the ASCO Nominating Committee

21st AACR—Bruce F. Cain Memorial Award for STI-571 team
The Cain Award recognizes an individual or research team for outstanding preclinical research leading to the discovery of a significant new therapeutic agent for the improved care of cancer patients. The AACR honors the research team that collectively developed the breakthrough drug STI-571 (Gleevec): Drs Alex Matter, Nicholas B. Lydon, Jürg Zimmerman and Elisabeth Buchdunger. Each of these scientists played a crucial role in developing the novel concepts that led to the successful development of the first ‘smart’ anticancer drug.

Fifth Pezcoller Foundation-AACR International Award for Cancer Research to the Director of the Uppsala branch of the Ludwig Institute
This award recognizes a scientist from anywhere in the world who has made a major scientific discovery in basic or translational cancer research. The AACR honors Dr Carl-Henrik Heldin for his outstanding contributions to our understanding of growth factor-mediated signal transduction in mammalian cells, in particular, platelet-derived growth factor (PDGF)-mediated signaling. From the beginning of his career, Dr Heldin focused on the mechanisms that control the growth of cells in culture, in the hope that this would lead to a greater understanding of the lack of growth control characteristics of cancer cells. Over the following two decades, Dr Heldin played a major role in unraveling the mysteries of mitogenic stimulation and the molecules that cells produce that govern this process. In 1994, Dr Heldin and his colleagues reported the characterization of type I receptors for transforming growth factor-ß (TGFß) and activin, and have since contributed regularly to the molecular clarification of TGFß signal transduction. Dr Heldin is director of the Uppsala branch of the Ludwig Institute for Cancer Research. This Institute was established in 1972, following a donation by Daniel K. Ludwig. The research within the Institute is carried out at ten different branches located in Brussels, Lausanne, London (two), Melbourne, New York, San Diego, São Paulo, Stockholm and Uppsala. In addition, the Institute has administrative offices in New York, London and Zürich.

The branch in Uppsala was established in 1986. The aim of its research is to elucidate the signaling pathways in cells that control cell growth. The group studies factors which stimulate or inhibit cell growth and tries to elucidate the molecular mechanism whereby such factors exert their effects on cells. The uncontrolled growth of cancer cells is to some extent due to constitutive activation of pathways that are controlled by growth stimulatory factors in normal cell or loss of components of growth inhibitory pathways. A goal is to develop clinically useful antagonists of growth factor action. The Uppsala branch is located at the Biomedical Center in Uppsala and operates under a contract with Uppsala University and the University Hospital.

ASCO Nominating Committee
Dr Martine Piccart, Brussels, has become a member of this key ASCO Committee whose task it is to develop a slate of candidates for elected positions including President-Elect, Secretary, Treasurer, Director and Nominating Committee members in accordance with the Bylaws.

Perhaps not everyone knows that...

...annual endoscopic surveillance of patients with atrophic gastritis or intestinal metaplasia can detect most new tumors at an early stage and lead to major improvements in survival. A large proportion of patients attending open access endoscopy have histological and gross pathological findings that are potentially premalignant, but the proportion of these patients who go on to develop malignancies and the timescale involved are uncertain. A study, from the Queen Elizabeth Hospital, Birmingham, UK, that aimed to discover the incidence of gastric cancers in this group, followed 166 patients with dysplasia, intestinal metaplasia, atrophic gastritis, foveolar hyperplasia, regenerative changes, polyps or ulcers, identified from a total of 1753 patients attending open access endoscopy. These 166 patients underwent endoscopy annually, with patients with ulcers being additionally re-examined at two-month intervals until ulcers healed. Cancers detected were treated by gastrectomy. Of the 1753 patients attending open access endoscopy 22 (1.3%) had gastric cancer. Over a 10-year period, 14 (8.4%) cancers were detected in the study population. These were of an earlier stage than those detected at open access (stage I and II, 67% versus 23%; P <0.05) and 5-year survival was significantly higher (50% versus 10%; P = 0.006). Given the large potential benefits of such surveillance programs, the authors call for further investigation [1].

...inactivation of the p53 tumor suppressor gene desensitizes cancer cells to hypoxic conditions and so appears to promote resistance to anti-angiogenic drugs. This is the conclusion of a study, from the Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada, that considered the responsiveness to anti-angiogenic combination therapy of mice bearing tumors derived from p53–/– HCT116 human colorectal cancer cells or isogenic p53+/+ tumors. The mice were treated with an antibody directed against vascular epithelial growth factor receptor-2 and low-dose vinblastine. After 42 days p53–/– tumors had increased seven-fold in size while those with functional p53 had only doubled. The authors propose the use of hypoxic cell cytotoxins, not affected by the presence of p53 mutations, as a means of improving anti-angiogenic therapy [2].

...a low-molecular mass compound named PRIMA-1 has been shown to restore sequence-specific DNA binding and the active conformation to mutant p53 proteins in vitro and in living cells. In a study from the Karolinska Institute, Sweden, PRIMA-1 was found to rescue both DNA contact and structural p53 mutants. Inhibition of tumor growth by p53 occurs primarily through the protein’s ability to induce apoptosis. The ability to reactivate p53 activity in tumor cells is, therefore, an attractive target for anticancer drug development. Screening compounds in the search for one that would restore p53 activity led to the discovery of PRIMA-1, which is able to trigger p53-dependent apoptosis in human tumor cell lines. Moreover, when injected into mice carrying human tumors, PRIMA-1 decreased tumor volume. The authors suggest that PRIMA-1 may provide the basis for the design of new anticancer drugs [3].

...children surviving acute lymphoblastic leukemia (ALL) after chemotherapy, including intrathecal and high-dose intravenous methotrexate, do not show major cognitive impairment. This is the conclusion of a study, from the University Hospital Groningen and the University of Maastricht, the Netherlands, that sought to assess persistent neuropsychological late effects in children treated for ALL with chemotherapy only. Twenty consecutive patients so treated underwent three evaluations, including 12 psychometric measures in addition to IQ, within a prospective-longitudinal design, beginning at diagnosis and extending to a median follow-up of 7 years. Results were compared with healthy controls and to patients with ALL treated on a previous chemotherapy-only protocol, and school achievement was also evaluated in patients and their siblings. At the last evaluation, patient scores compared with control scores were only found to be significantly lower for two of 14 cognitive measures, intelligence and attention measure. No major differences were seen between patients and siblings in school achievement [4].

...the risk of female rheumatoid arthritis (RA) patients developing severe disease is increased in those who have the glutathione S-transferase polymorphism, GSTM1-null, and who have also smoked. In an attempt to analyze the association between GSTM1 genotype, smoking history and disease severity in a cross-sectional retrospective study, researchers at the North Staffordshire Hospital, Stoke-on-Trent, UK, enrolled 164 female RA patients who had the disease for at least 5 years. Disease severity was assessed using the Health Assessment Questionnaire (HAQ), radiographic analysis using Larsen, and serum rheumatoid factor (RF) levels. Current and past smoking history was quantified and categorized as ‘never smoked’, ‘past smoker’ or ‘current smoker’. The GSTM1 genotype was identified by extracting leukocyte DNA and using a PCR assay to classify patients to: GSTM1-1, the functional gene; and GSTM1-null, the deleted gene. Of the 164 women with RA, 51.3% were never smokers, 29.9% were current smokers and 58.5% had the GSTM1-null genotype. Past and current smokers had significantly higher Larsen and HAQ scores than non-smokers, indicating more severe disease in RA patients with a smoking history. While the Larsen and HAQ scores did not significantly differ between GSTM1-1 and GSTM1-null patients after adjustment for age and disease duration, GSTM1-null patients with a history of smoking had significantly higher Larsen and HAQ scores than GSTM1-null patients who had never smoked. Radiographic outcome was worse in GSTM1-null patients with a smoking history than in GSTM1-1 patients with a smoking history. GSTM1 status and smoking history were also strongly associated with RF status and concentration [5].

...studies that assess the use of biological indicators of health status to motivate people to adopt healthier attitudes and lifestyles have produced mixed results, but when analyzed together a positive pattern can be seen. This is the conclusion of an analysis, from the Center for Health Studies of the Group Health Cooperative in Seattle, WA, USA, of eight such randomized studies. Those studies that did not show a significant effect on motivation or behavior change used a single health indicator, tested on one occasion. In contrast, studies that showed positive results used a single indicator assessed at multiple visits or multiple indicators assessed at a single visit. The health indicators reviewed included cholesterol level, carbon monoxide level, lung cancer susceptibility genes, depressed breathing function and other pulmonary symptoms, and physical fitness. The studies explored the effects of health indicators on tobacco use, dietary change and physical activity. The number of participants in each study varied from 90 to >2000, but the authors note that conclusions are limited by the dearth of randomized studies on this subject [6].

...downsizing of personnel and the ensuing reorganization may adversely affect the health of personnel. This is the tentative conclusion of a study, from the Institute of Psychosocial Factors of Health, Stockholm, Sweden, that aimed to assess potential physiological changes associated with downsizing/reorganization in the healthcare sector. In the single institute studied, a regional hospital, personnel reductions between 1995 and 1997 corresponded to one fifth of the personnel. In a longitudinal study, female personnel had blood sampled twice (8 am and 4 pm) during a working day in 1997 (in connection with the last completed round of personnel redundancies) and 1 year later in 1998. The participants were 31 women (82% of those initially sampled); there were 14 registered nurses, 11 assistant nurses and six medical secretaries. There were no additional losses during follow-up. Outcome variables were; changes in the difference in serum cortisol levels between the morning and afternoon, and in serum/plasma concentrations of immunoglobulin G (IgG), estradiol, dehydroepiandrosterone sulphate (DHEAS), prolactin and apolipoproteins AI and B. Significantly decreased serum/plasma concentrations of IgG (P <0.001), apolipoprotein AI (P <0.001) and estradiol (P <0.001) were observed. The difference between morning and afternoon serum cortisol decreased significantly (P = 0.05), but no significant changes were observed regarding prolactin, DHEAS and apolipoprotein B. The authors suggest that these results could be an indication that protective and anabolic functions had suffered in these remaining ‘aging’ female work groups. The conclusions are tentative, given the small size of the sample and the lack of a control group, but the findings do suggest the significance of studies of physiological changes possibly associated with restructuring of the healthcare sector [7].

References

1. Whiting JL, Sigurdsson A, Rowlands DC et al. The long term results of endoscopic surveillance of premalignant gastric lesions. Gut 2002; 50: 378–381.[Abstract/Free Full Text]

2. Yu JL, Rak JW, Coomber BL et al. Effect of p53 status on tumor response to antiangiogenic therapy. Science 2002; 295: 1526–1528.[Abstract/Free Full Text]

3. Bykov VJ, Issaeva N, Shilov A et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nature Med 2002; 8: 282–288.[ISI][Medline]

4. Kingma A, Van Dommelen RI, Mooyaart EL et al. No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: a prospective longitudinal study. J Pediatr Hematol/Oncol 2002; 24: 106–114.[ISI][Medline]

5. Mattey DL, Hutchinson D, Dawes PT et al. Smoking and disease severity in rheumatoid arthritis: association with polymorphism at the glutathione S-transferase M1 locus. Arthritis Rheum 2002; 46: 640–646.[ISI][Medline]

6. McClure JB. Are biomarkers useful treatment aids for promoting health behavior change? An empirical review. Am J Prev Med 2002; 22: 200–207.[ISI][Medline]

7. Hertting A, Theorell T. Physiological changes associated with downsizing of personnel and reorganisation in the health care sector. Psychother Psychosom 2002, 71: 117–122.[ISI][Medline]





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