Do you Euro?

Following up on last month’s news, one has by now become accustomed to this new currency. Its introduction, as we write, seems a success, with >85% of the old currencies already withdrawn by mid-January, while it had been expected that double circulation would last until the end of January and was actually authorized in many countries until the middle or end of February. Physicians have also had to face some adaptation issues, in France only 25% had modified their computer programs in order to be able to send their bills to the Social Security in Euros by mid-January. They were given a further delay for this change until February 17. While complaints of ‘hidden’ price hikes have been common, one can be certain that this will not be possible for medical bills. At least in France, where GPs have been going from strike to strike in order to influence the government, which refuses to adapt the basic cost of a consultation, which the GPs would like to see increased to i20. How does that compare with other countries? This point is never mentioned in the French negotiations... On the other hand one can read in the January newspapers that Irish authorities have decided to verify the way doctors have "rounded up" their figures, as some honoraria might have been unilaterally "improved".

Pharma industry tricks continue in biotechnology

We recently reported on two UK charities and their merger, in the meantime industry has continued its ‘consolidation’. The stock market reacted violently at the end of the year to the news about cloning successes and problems. A bumpy ride last year has left biotech companies on more realistic price/earnings multiples. In December, Amgen/Immunex, Millennium/Cor and MedImmune/Aviron deals were struck, as reported in many newspapers. In the UK, the Financial Times of 7 January 2002 discussed the notion that the need to augment product pipelines, reduce the inefficiencies of multiple corporate overheads and increase liquidity to attract big investors may drive further merger and acquisition activity. The example of Amgen/Immunex, in particular, was believed to show that biotech companies had started to act more like the big pharmaceuticals companies by buying in growth products. This particular merger created a group, of ~i84 billion, starting to approach ‘big pharma’ in size.

Pharma unhappy, of course, but the Brazilian government continues to promote generics

One can read on http://www.progenericos.org.br/ that the Brazilian National Sanitary Surveillance Agency has decided to allow the production of 41 generics of various hormones, decreasing the cost to the consumer by at least 40%. This list will also include some bisphosphonates and is enforced as of early January 2002.

Stem cells: more about the ‘monster of Loch Ness’

Fundamental ethical problems are created by the understandable desire of researchers to use their fabulous tools to unravel more and more of the mysteries of life. But the debate becomes complex when one completely mixes the issues, and confuses the use of pluripotential cells obtained from live blood donors, surgical specimens or brain-dead people, and the use of true embryonal stem cells. This is the real issue, although one can potentially argue that it is possible to reverse the cell’s differentiation signals to such an extent as to obtain true stem cells (i.e. the initial result of the fusion of a spermatozoon and an ovocyte) and recreate a human being, a true clone.

In Switzerland last autumn some debate went on as the Swiss National Funds (SNF) committee approved the plans of a group, led by Karl-Heinz Kraus, of the University of Geneva’s University hospital, and Marisa Jaconi, to work with human embryonic stem cells. Issue 48/2001 of the Bulletin des Médecins Suisses contains in both French and German a long and informative statement of the Swiss National Ethics Committee for Human Medicine. To this reader it seems that besides the obvious issue of potential cloning of human beings, the main debate centers around the ethicality of using cells that would have been the source of a human being. Indeed, they come from ‘surplus’ embryos, at the blastocyst stage, obtained after an in vitro fertilization. As mentioned previously in Annals, there are many sources of ‘embryonic’ cell lines, and indeed the Swiss researchers are going to import such cells. One of the main goals of the project is to continue to work in the area of transforming stem cells into heart tissue, something accomplished by American and Israeli researchers in the summer of 2001. Kraus, however, as reported in the Swiss press, believes that what the media call adult stem cells (and we would call pluripotential cells), which can be harvested without harm to the donor, have been underestimated in their usefulness. Such cells could be used, for example, to ‘create’ liver cells, and it has been shown that skin stem cells can produce nerve cells.

And where is "Nessie" in all this? These news items come and go in the press, often when fortunately no major disaster or ‘peace-keeping action’ can be reported. And this is what used to happen with "Nessie".

But the discussion is also related to some real news, such as the November 2001 announcement of human cloning, which was actually not much at all. The Advanced Cell Technology team transferred nuclei from adult skin and ovarian cells into human eggs that had been stripped of their own chromosomes. Eleven out of 19 eggs appeared to undergo the early stages of embryo development by forming a ‘pronucleus’, a structure that forms in eggs fertilized with sperm. Two went on to divide into four cells and one into six cells.

In the 2 January 2002 issue of Proc Natl Acad Sci USA, researchers at Harvard Medical School announced that they had used embryonic mouse stem cells to relieve symptoms of Parkinson’s disease in rats. They demonstrated that the cells can be turned into neurons that make dopamine. Isacson and colleagues took stem cells from early mouse embryos, called blastocysts, and injected them into the brains of 25 experimental rats. The 14 rats whose condition improved all had new brain cells, and testing showed the cells had developed into neurons and other brain cells from the mouse stem cell transplants. The obvious negative side is that five of the rats died and turned out to have teratomas at the injection site. This did not however stop the Swedish Medical Research Council from establishing, on the 3 January 2002, that the use of embryonal stem cells was ethically permissible. Meanwhile we learn that Dolly, the cloned sheep, has arthritis at age 5 and this leads many to question the value of cloning in animal farming.

Lung cancer: more light on the differences

Non-small-cell lung cancer is represented mainly by adenocarcinomas and squamous cell carcinomas. A debate about differential chemosensitivity among these two types of tumor exists, and one difficulty lies in the more or less poorly differentiated forms which are diagnosed as one or the other by the pathologist, thus muddying the water. Mainly peripheral, with frequent K-ras mutations, the adenocarcinomas have p53 mutations less often compared with the more centrally located squamous tumors. In Proc Natl Acad Sci USA of the 18 December 2001, Mariana Nacht showed that adenocarcinomas are characterized by a high level of expression of proteins seen in small airways or related to the immune system, while squamous tumors overexpress genes related to detoxification and antioxidant properties. Such data, along with molecular characterization of the tumors, might help in finding appropriate treatment for this disease, whose incidence will rise before finally dropping if anti-tobacco campaigns are successful.

Tomato juice and prostate cancer: or is it about vodka?

In Men’s Health January 2002 one can read that American researchers might have confirmed some medical virtues of tomatoes. While one remembers that ß-carotene has been described as a prostate cancer risk-increasing agent, it seems that a glass of tomato juice a day after the diagnosis of prostate cancer improved some cellular functions and aspects in these men. One wonders if the main effect was not related to the absence of alcohol in this tomato juice as compared to the Bloody Marys consumed previously...

About failures in medical systems

Finland is proud of having a medical care system which is highly cost-efficient, but its cost-efficiency comes with a high price as nurses move away to other countries where they are better paid and it has become more and more difficult to recruit physicians to man the ‘health stations’ around the country. This has lead to recent strikes, and some salaries have been increased. Meanwhile, French health personnel including physicians continue their strikes as the implementation of the French law calling for a 35-h working week is seen as impossible to implement in the healthcare system without major changes including salary improvements. These strikes mean that right now in many French hospitals emergency admissions have to wait for 12–24 h before admission on to a ward, usually staying in a corridor on a stretcher. But this does not stop the UK, which sent to France the first nine patients to have their treatment abroad paid for by the National Health Service. The patients are having their travel, surgery and aftercare costs paid for by the health service. The news in the Financial Times of the 18 January 2002 even included a statement from a UK government official saying that "...of course, patients will be guaranteed a decent cup of tea". No comment. Up to 200 more patients from southern England could follow the first nine in the next 3 months to French and German hospitals as a model contract is developed that the NHS can use more widely. And in Switzerland the implementation of a general law which does not allow workers to work for more than 10 h in a row is putting private clinics into difficulty, as nurses used to have different schedules, often of 12 hours, allowing them to have short working weeks. The law is not implemented in public hospitals, which the legislator ex-empted, and of course clinics are appealing on the grounds of discrimination. The Swiss health law calls for an equal treatment of the public and private sector...and this of course has yet to be achieved, and may never be achieved.

Erbitux® is not a herbal medicine, but maybe some company managers need herbal aid...

IMC-C225, the antibody directed against the EGF receptor made by ImClone systems Inc. was due for co-development with Bristol-Myers Squibb Co. The latter had agreed to pay US$1 billion for a 20% share of ImClone, giving it access to Erbitux. But the Food and Drug Administration (FDA) refused an application and early this year the shares of ImClone took a plunge. But the worst was yet to come. On its black Friday, 18 January 2002, ImClone, as reported in the Financial Times, gained the dubious distinction of joining Enron as the target of a congressional investigation. The House of Representatives’ Energy and Commerce Committee said it had sent letters of inquiry to the New York-based company regarding its Erbitux cancer drug. ImClone’s shares tumbled 43%. The House committee has asked whether ImClone’s chief executive, Sam Waksal, and the chief operating officer and his brother, Harlan Waksal, were aware of the FDA’s concerns about the treatment, but failed to inform shareholders and the company’s partner, Bristol-Myers Squibb. The committee’s letter states that it was concerned that the company had not provided accurate or complete descriptions of the FDA’s actions to the Securities and Exchange Commission (SEC). The committee has also requested information from Bristol-Myers Squibb and the FDA. It asked the FDA if it has had contact with the SEC regarding the announcement of the rejection of Erbitux. ImClone, Bristol-Myers Squibb and the FDA have until the end of the month to respond.

Awards, appointments

We are happy to announce to all readers that the President of AIOM (Associazione Italiana di Oncologia Medica) for 2001–2003 is Francesco Cognetti; well known to all ESMO members as a past member of the Executive and current ESMO National Representative for Italy. The President-elect is Roberto Labianca, who has several roles within ESMO, one of them as an Associate Editor of Annals of Oncology.

Perhaps not everyone knows that...

...gene-expression profiling using microarray analysis combined with a supervised machine learning prediction method identified two categories of patients with diffuse large B-cell lymphoma (DLBCL) with very different 5-year overall survival rates. Diffuse large B-cell lymphoma is the most common lymphoid malignancy in adults, and over 50% of patients die from the disease. Current prognostic models, such as the International Prognostic Index (IPI), are based on pre-treatment characteristics but identify neither specific therapeutic targets or the molecular basis of clinical heterogeneity. However, gene activities that determine the biological behavior of a tumor are more likely to reflect its aggressiveness. Researchers at the Whitehead Institute for Biomedical Re-search, Cambridge, Massachusetts, and colleagues analyzed the expression of 6817 genes in tissues from patients with DLBCL who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. These authors found that, based on the gene expression profiles, they could identify two groups with 5-year overall survival rates of 70% and 12%. The developed model also delineated patients within specific IPI risk categories who were likely to die or be cured [1].

...recent respiratory disease and persistent proinflammatory alveolar macrophage (AM) activity are associated with lung disease following hematopoietic stem cell transplantation (SCT). These are the conclusions of a study that aimed to test whether a proinflammatory alveolar microenvironment, reflected in AM cytokine production would predispose patients to pulmonary complications that could compromise the success of SCT. Alveolar macrophages were isolated from adult SCT recipients before SCT (n = 32) and during post-transplant pancytopenia (n = 23). The concentrations of tumor necrosis factor (TNF)-{alpha}, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-1ß, IL-6 and IL-8 in 24-h AM culture medium were measured by ELISA. Results were compared with both the occurrence of post-SCT lung disease and with subjects’ previous respiratory histories. The 11 patients who developed lung disease within 6 months of SCT showed higher median pre-transplant AM TNF{alpha} [8 (Interquartile range, IQR 1–8) versus 2 ng/106AM (IQR 1–5), P = 0.01, median difference (D) 3, 95% confidence interval (CI) 0.1–7], GM-CSF [5 (IQR 0.7–8) versus 0.2 ng/106AM (IQR 0.1–0.8), P = 0.006, D 4, 95% CI 0.5–7] and IL-6 [0.5 (IQR 0.1–1) versus 0.1 ng/106AM (IQR 0.02–0.3), P = 0.049, D 0.3, 95% CI 0.0002–1] production than the other subjects. During pancytopenia, high AM GM-CSF production again predicted later lung disease, and a history of recent chest disease was also associated with high AM TNF-{alpha} and GM-CSF production and post-SCT lung disease [2].

...gastroesophageal reflux is strongly associated with the risk of esophageal adenocarcinoma, and to a lesser extent, with gastric cardia adenocarcinoma. Moreover, these risks remain increased after antireflux surgery. These are the conclusions of a Swedish population-based retrospective cohort study that aimed to consider these risks, specifically the role of antireflux surgery. The study identified, in the Swedish Inpatient Register, two cohorts, one of 35 274 male and 31 691 female patients with a discharge diagnosis of gastroesophageal reflux diseases, and another of 6406 male and 4671 female patients who underwent antireflux surgery. Follow-up was achieved through linkage with the several nationwide registers and the relative risk of upper gastrointestinal cancers was estimated by means of standardized incidence ratios (SIR), using the general Swedish population as a reference. Among the male patients who did not have surgery 37 esophageal and 36 gastric cardia adenocarcinomas were observed (SIR 6.3, 95% CI 4.5–8.7; SIR 2.4, 95% CI 1.7–3.3, respectively), with the SIR for esophageal adenocarcinoma increasing with follow-up time (P = 0.03 for trend). The male patients who had undergone antireflux surgeries also showed elevated risks (16 esophageal adenocarcinoma, SIR 14.1, 95% CI 8.0–22.8; 15 gastric cardia adenocarcinomas, SIR 5.3, 95% CI 3.0–8.7) which remained elevated with time after surgery. The risk patterns were similar for women, but the numbers of cases were much smaller [3].

...while both conventional rectal cancer surgery and total mesorectal excision (TME) decrease sexual function, TME offers a significant advantage with regard to preservation of postoperative sexual function in men. This is among the conclusions of a study, from the Inselspital, University of Bern, that sought to consider the effect of TME on autonomic pelvic nerve function. Patients with resected primary rectal cancer, both with (n = 31) and without (n = 29) TME, were interviewed by means of a questionnaire asking about preoperative and postoperative urinary bladder and genital function. Patients treated with TME were older and had a lower level of anastomosis than patients treated without TME. Male patients reported the following sexual functions before operation/after operation with TME versus without it: interest in sex 63/37% versus 80/40%; sexually active 53/22% versus 67/7%; impotence 58/26% versus 75/6%; ability to have intercourse 67/29% versus 75/13%; and ability to achieve orgasm 76/47% versus 88/13% [4].

...women may need further information about breast cancer symptoms to assist in symptom recognition, as well as encouragement to seek medical advice if a symptom is ambiguous, since failure to recognize symptoms, particularly in the absence of a breast lump may lead to delays in seeking medical advice. This is the conclusion of a qualitative analysis of semistructured interviews, from the Adamson Centre for Mental Health, St Thomas’s Hospital, London, which sought to consider the factors that influence general practitioner consultation by women with breast cancer symptoms. From 185 women recruited to a larger study, 46 with newly diagnosed breast cancer were interviewed 8 weeks after diagnosis. These women were divided into two groups: 15 had sought advice from their GP within 2 weeks of finding symptoms, but the remaining 31 had waited 12 weeks or more before seeing their doctor. The women who presented promptly to GPs had recognized the seriousness of the symptom they had discovered more quickly than those in the other group. This perception of seriousness was influenced by the nature of the initial symptom and how far it matched their expectations of breast cancer as a painless breast lump, with 20 of the women in the delayed group not having such a lump [5].

...measuring brain tissue spin-lattice relaxation time (T1) as a surrogate for radiation effect has shown that human white matter is not sensitive to radiation therapy of <20 Gy, and that grey matter T1 is unchanged over the dose range used to treat human brain tumors. These findings are among the results of a study, from the University of Tennessee School of Medicine, that used quantitative magnetic resonance imaging (MRI) to consider whether fractionated radiation therapy within a therapeutic dose range is associated with a dose-related change in normal brain. Quantitative MRI was used to measure the T1 values of 33 patients before treatment and at various times during and after radiation therapy. Changes in white-matter and grey-matter T1 values were analyzed as a function of radiation dose and time since treatment, controlling for patient age and tumor site. Dose levels of >20 Gy were associated with a dose-dependent decrease in white-matter T1 over time, which became significant 6 months after treatment. No significant change in the T1 of grey matter was observed over time, at radiation therapy doses of <60 Gy. The authors note, however, that grey matter in close proximity to the tumor had a lower T1 prior to therapy [6].

...fresh oregano has 42x more antioxidant activity than apples, 30x more than potatoes and 12x more than oranges. This is among the findings of a chemical analysis, from the US Department of Agriculture, Agricultural Research Service, of the antioxidant capacities (oxygen radical absorbance capacity, ORAC) and total phenolic contents in extracts of 27 culinary and 12 medicinal herbs. ORAC values and total phenolic content for the culinary herbs ranged from 2.35 to 92.18 µmol of Trolox equivalent (TE)/g of fresh weight and 0.26–17.51 mg of garlic acid equivalent (GAE)/g of fresh weight, respectively. These were much higher than values found in the medicinal herbs. Among the more common herbs found to have strong antioxidant activity were dill, thyme, rosemary and peppermint. A linear relationship was found between ORAC values and total phenolic contents for both the culinary (R = 0.986) and the medicinal herbs (R = 0.919) [7].

...television news may skew viewer perceptions of the risks associated with traumatic injuries, as some types of events receive disproportionately more news coverage than others. A study, from UCLA School of Public Health, that identified the underlying causes of death or injury in each of 828 local television news stories broadcast in Los Angeles during late 1996 or early 1997 that concerned recent traumatic injuries or deaths in Los Angeles County, concluded that local television news tends strongly to present only those events concerned with death or injury that are visually compelling. Nearly all traumatic deaths by homicide, air travel, fire, natural or environmental factors and law-enforcement activity drew coverage, accounting for 65.6% of all traumatic deaths in the news, while constituting just 31.4% of actual traumatic deaths in the county. In contrast, deaths due to motor vehicle crashes were portrayed about a third less than actual occurrence, and all other causes of traumatic death were portrayed in much lower proportion to actual occurrence. In reporting stories involving non-fatal injuries, local TV news crews covered about one in five assaults resulting in hospitalization. Meanwhile, injuries due to fires and water travel were portrayed proportionally more often than any other cause of injury. Under-represented injuries included accidental poisonings, motor vehicle non-traffic events, falls, natural or environmental factors, near drownings and injuries related to falling objects, machinery, explosions or electricity [8].



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Francesco Cognetti.

 
References

1. Shipp MA, Ross KN, Tamayo P et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002; 8: 68–74.[ISI][Medline]

2. Whittle AT, Davis M, Shovlin CL et al. Alveolar macrophage activity and the pulmonary complications of haematopoietic stem cell transplantation. Thorax 2001; 56: 941–946.[Abstract/Free Full Text]

3. Ye W, Chow W-H, Lagergren J et al. Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery. Gastroenterology 2001; 121: 1286–1293.[ISI][Medline]

4. Maurer CA, Z’Graggen K, Renzulli P et al. Total mesorectal excision preserves male genital function compared with conventional rectal cancer surgery. Br J Surg 2001; 88: 1501–1505.[ISI][Medline]

5. Burgess C, Hunter MS, Ramirez AJ. A qualitative study of delay among women reporting symptoms of breast cancer. Br J Gen Pract 2001; 51: 967–971.[ISI][Medline]

6. Steen RG, Spence D, Wu S et al. Effect of therapeutic ionizing radiation on the human brain. Ann Neurol 2001; 50: 787–795.[ISI][Medline]

7. Zheng W, Wang SY. Antioxidant activity and phenolic compounds in selected herbs. J Agric Food Chem 2001; 49: 5165–5170.[ISI][Medline]

8. McArthur DL, Magana D, Peek-Asa C, Kraus JF. Local television news coverage of traumatic deaths and injuries. West J Med 2001; 175: 380–384.[ISI][Medline]





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