G protein in very low birth-

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1   Zeidler M, Sellar RJ, Collie DA, et al. The             treatment of the samples4 we found out                   Pediatrics, First Department of Pediatrics,
    pulvinar sign on magnetic resonance imaging                                                                      Budapest, H-1083, Hungary; First Department of
                                                            the GNB3 C825T polymorphism                              Pediatrics and Second Department of Gynecology
    in variant Creutzfeldt-Jakob disease. Lancet
    2000; 355: 1412–18.                                     according to Siffert and colleagues.2                    and Obstetrics, Semmelweis University, Hungary;
2   Will RG, Ironside JW, Zeidler M, et al. A               Continuous variables were compared by                    and Buda Children’s Hospital, PKU and Metabolic
                                                                                                                     Screening Center, Budapest
    new variant of Creutzfeldt-Jakob disease in             two-sided t tests. Categorical data were                 (e-mail: vasbar@gyer1.sote.hu)
    the UK. Lancet 1996; 347: 921–25.                       assessed by 2 test.
3   Chazot G, Broussolle E, Lapras CI,
                                                               Birthweight, gestational age, and                     1   Hocher B, Slowinski T, Stolze T, Pleschka A,
    Blattler T, Aguzzi A, Kopp N. New variant
    of Creutzfeldt-Jakob disease in a 26-year-old           genotype of full-term and preterm                            Neumayer HH, Halle H. Association of
    French man. Lancet 1996; 347: 1181.                     neonates are given in the table. The T                       maternal G protein b3 subunit 825 T allelle
                                                                                                                         with low birthweight. Lancet 2000; 355:
4   Bahn MM, Kido DK, Lin W, Pearlman AL.                   allele frequency of the control and                          1241–42.
    Brain magnetic resonance diffusion                      VLBW subjects did not differ. The
    abnormalities in Creutzfeldt-Jakob disease.                                                                      2   Siffert W, Rosskopf D, Siffert G, et al.
    Arch Neurol 1997; 54: 1411–15.                          relative number of TC and CC                                 Association of a human G-protein beta3
                                                            genotypes did not differ between control                     subunit variant with hypertension. Nat Genet
                                                                                                                         1998; 1: 45–48.
                                                            infants, infants of appropriate weight for
                                                                                                                     3   Curhan GC, Willett WV, Rimm EB,
G protein in very low birth-                                gestational age, and infants small for                       Spiegelman D, Ascherio AL, Stampfer MJ.
weight infants                                              gestational age. There was also no                           Birth weight and adult hypertension, diabetes
                                                            difference in the birthweight of babies                      mellitus, and obesity in US men. Circulation
                                                            with TC and CC genotype (mean [SD]:                          1996; 94: 3246–50.
Sir—Berthold Hocher and colleagues
                                                                                                                     4   Szalai Czinner A, Révai K. The frequency of
(April 8, p 1241)1 report, that the birth-                  1230 [250] g and 1197 [64] g,                                medium chain acyl CoA dehydrogenase
weight of otherwise healthy full-term                       respectively). This finding is in                            G985 mutation in Hungary. Eur J Pediatr
neonates is lower, when the maternal G                      accordance with the observation of                           1996; 155: 256.
protein 3 subunit 825T allele (GNB3                         Hocher and colleagues, who did not find
825T) is present. They did not find any                     any effect of presence of GNB3 825T on
association between the genotype of the                     birthweight in healthy full-term babies.
babies and their birthweight. However,                         The TT genotype was more frequent                     Information on
premature babies were excluded from                         in the control group (p<0·01), than in
their study.                                                VLBW babies. Samples for neonatal                        thiazolidinediones
   The presence of GNB3 825T is                             screening programme are collected after                  Sir—Kristina Schoonjans and Johan
associated with higher risk of                              the fourth postnatal day from VLBW                       Auwerx stated in their review (March
hypertension.2 The prevalence of                            babies and we could not recruit those                    18, p 1008)1 of the thiazolidinediones (a
hypertension is also higher in those who                    who died during the first postnatal week.                family of diabetes drugs) that “much of
had been born with a low birthweight.3                      Therefore, we speculate that the absence                 the information discussed here has had
In our study, we investigated, in very low                  of TT genotype in VLBW infants might                     to come from company websites”. We
birthweight (VLBW) infants (birth-                          be attributed at least in part to a higher               sympathise with the authors’ difficulty in
weight <1500 g), whether their reported                     susceptibility of VLBW infants with TT                   finding peer-reviewed data on these
higher     adulthood     prevalence      of                 genotype towards perinatal death. To                     drugs. This stems from the failure of
hypertension is associated with a higher                    answer this question studies are needed                  drug companies to publish their
frequency of GNB3 825T.                                     to analyse the survival rate of VLBW                     findings—it appears that only one of 11
   We reviewed the medical records of                       infants      with     different     GNB3                 efficacy studies submitted to the US
142 VLBW singleton infants (gestational                     polymorphisms.        Our     data,    the               Food and Drug Administration (FDA)
age 26–36 weeks). They were born in                         significance of which needs to be                        as part of the approval packages for
1999 and treated at the Perinatal                           clarified, indicate that the high                        rosiglitazone and pioglitazone has been
Intensive Care Unit at the second                           prevalence of hypertension in people                     published.
Department of Obstetrics, Semmelweis                        who were premature at birth is probably                     However, drug company websites are
University, Semmelweis, Hungary. We                         not associated with the higher frequency                 not the only, and certainly not the best,
contacted the Neonatal Metabolic                            of G protein 3 subunit (825T) allele.                    place to find unpublished data on drugs.
Screening Programme and asked for                                                                                    Consulting      readily    available    US
                                                            This study was supported by OTKA Grants
dried blood-spot samples of the chosen                      T031850, F032024. We thank Andrea Horvárth               governmental sources on the internet
babies. The samples of 97 babies were                       for the collection of samples and Ágnes Czárán           can lead to different conclusions
available: 26 were born small for                           and Szilvia Kruspér for technical assistance.
                                                                                                                     regarding drug safety and efficacy. Using
gestational age (per centile weight <5%),                   *Barna Vásárhelyi, István Kocsis,                        FDA data sources, we have just
while 71 were of appropriate weight for                     Ágnes Schuler, András Nobilis,                           completed our own assessment of the
gestational age. Dried blood spots of 101                   Tivadar Tulassay                                         thiazolinediones. This research resulted
term neonates (birthweight >2500 g)                         *Joint Research Programme of the Hungarian               in a petition to the FDA to relabel all
served as controls. After the pre-                          Academy of Sciences and the First Department of
                                                                                                                     three drugs to state that they are not only
                                                                                                                     less efficacious than already-approved
                                                                                                                     drugs, but appear to have class toxicities,
                                                        Control (n=101)      VLBW
                                                                                                                     particularly cardiac failure (www.citizen.
                                                                             SGA (n=26)         AGA (n=71)           org.hrg/PUBLICATIONS/1514.htm;
Mean (SD) birthweight (g)                               3421 (376)*          1240 (254)         1195 (244)           accessed June 23, 2000), a serious
Mean (SD) gestational age (weeks)                          40 (2·4)*            33 (2·7)           29 (1·7)          finding not previously adequately
                                                                                                                     acknowledged in the product labelling or
TT                                                         16*                   0                  0                on the company websites.
TC                                                         42                   21                 46                   These conclusions could never have
CC                                                         43                    5                 25                been reached had we depended upon
Frequency of GNB3 825T                                     37%                  40%                32%               the company websites alone. Unlike the
*p<0·01 compared with the VLBW infants; VLBW=very low birth weight; SGA=small for gestational age; AGA=appropriate   company websites, which provide only
for gestational age.                                                                                                 the product labelling and superficial
Birthweight, gestational age, and genotype of VLBW infants and control infants                                       information about the drugs, the FDA

254                                                                                                                        THE LANCET • Vol 356 • July 15, 2000

For personal use only. Not to be reproduced without permission of The Lancet.

website includes detailed summaries and            Recognising lesions on                             number of adenomas found other
assessments of the actual data submitted                                                              than to say that polyps were found in
in support of the New Drug Application.            colonoscopy                                        26·9% of cases. In comparison,
Reviews of pre-clinical studies and                Sir—We agree with B J Rembacken and                adenomas were found in 32·1% of
clinical trials submitted to the FDA               colleagues (April 8, p 1211)1 that                 examinations in Leeds. A possible
for troglitazone, rosiglitazone, and               training in the recognition of flat,               reason for this discrepancy is that dye
pioglitazone     were      available    to         elevated, and depressed lesions at                 spraying techniques were not used in
Schoonjans and Auwerx through a                    colonoscopy is important in the                    Glasgow.
Freedom of Information Act (FOIA)                  detection of early colorectal cancer.                 In contrast to the series from
request       (www.fda.gov/foi/foia2.htm;          However, we suspect that these lesions             Glasgow, which excluded lesions with
accessed June 23, 2000). For some                  have been observed previously by UK                severe dysplasia or intramucosal
drugs approved after 1997, reviews can             colonoscopists, but not reported as                carcinoma, we included these lesions in
be downloaded directly from the                    such. In a study of over 2000                      our analysis. We referred to these lesions
agency’s web site (www.fda.gov/                    colonoscopies done between 1990 and                as early cancers, because failure to
cder/approval/index.htm; accessed June             1998 we identified nine flat or depressed          detect and treat such lesions is likely to
28, 2000). Use of the FOIA is not                  cancers, three of which were less than             lead to advanced colorectal carcinoma.
limited to US citizens.                            10 mm in diameter.2 This compares                  This was clearly stated in our results
   In the past, FDA clinical, statistical,         with four flat or depressed cancers in the         section.
and pharmacology reviews were only                 series of 1000 colonoscopies done by                  In their article, Smith and colleagues
made publicly available after a drug was           Rembacken and colleagues. Given the                classified lesions as pendunculated,
approved, severely limiting scientific             indications for colonoscopy in the study           villous, and flat compared with
debate over the appropriateness of drug            by Rembacken and colleagues we were                polypoid, depressed, and flat in our
approval. As a result of a lawsuit we              surprised that only 3% of patients had a           study. It is therefore interesting to learn
brought against the agency, the materials          colorectal cancer diagnosed. As well as            that a similar proportion of early
distributed to FDA Advisory Committee              training endoscopists in recognition of            colorectal cancers (T1 stage) where flat
members before approval, including                 lesions, it is also critical that clinicians       or depressed in Glasgow (nine of 18)
summaries of the FDA reviews, are now              are trained to target this important               compared with Leeds (four of six).
posted on the internet the day before              resource to the right population, in                  However, the recognition that early
the Advisory Committee meeting                     respect to age and indication. Mean age            cancers may appear flat or depressed has
(www.fda.gov/ohrms/dockets/ac/00mtbc               of patients undergoing colonoscopy in              important implications beyond semantic
.htm; accessed June 23, 2000). The                 the study by Rembacken and colleagues              definitions of flat, villous, and sessile.
transcripts of these FDA Advisory                  was only 59 years .                                Until now, most early carcinomas were
Committee meetings are another                                                                        thought to be polypoid. From the
                                                   G A Smith, S MacKenzie, P J O’Dwyer
valuable     source     of    information                                                             realisation that non-polypoid neoplasia
                                                   Department of Surgery, Western Infirmary,
(www.fda.gov/foi/electrr.htm; accessed             Glasgow G11 6NT, UK                                account for a large proportion of early
June 23, 2000).                                                                                       colorectal cancers follow two important
   The failure of Schoonjans and                   1   Rembacken BJ, Fujii T, Cairns A, et al. Flat   conclusions. First, endoscopists should
Auwerx to consult these free sources,                  and depressed colonic neoplasms: a             be trained in the techniques necessary
and their reliance instead on self-serving             prospective study of 1000 colonoscopies in     for their detection and management.
                                                       the UK. Lancet 2000; 355: 1211–14.
data from the company, seriously                                                                      Second, gastroenterologists and hospital
                                                   2   Smith GA, Oien KA, O’Dwyer PJ.
undermines the credibility of their                    Frequency of early colorectal cancer in        managers may reconsider the role of
review.                                                patients undergoing colonoscopy. Br J Surg     radiology in investigating the large
                                                       1999; 86: 1328–31.                             bowel as contrast studies and a
Public Citizen’s Health Research Group is a
non-profit, consumer research and advocacy                                                            substantial proportion of cancers in their
                                                   Authors’ reply
                                                                                                      early and curable stages may be missed
*Sidney M Wolfe, Peter Lurie,                      Sir—In planning our study, we decided              by virtual colonoscopy.
Larry D Sasich, Elizabeth Barbehenn                not to preselect patients to allow                    We disagree with the implication that
Public Citizen’s Health Research Group,            comparisons between different units                colonoscopy is a limited resource that
1600 20th Street NW, Washington,                   both within and outside the UK. It is              should be targeted on elderly patients.
DC 20009-1001, USA                                                                                    Colonoscopy is superior to radiological
                                                   not surprising that in the unusual series
                                                   done in Glasgow, UK, by G A Smith                  methods in detecting early cancer and in
1   Schoonjans K, Auwerx J. Thiazolidinediones:
    an update. Lancet 2000; 355: 1008–10.          and colleagues2 there was a slightly               the diagnosis of such mucosal diseases
                                                   higher proportion of colorectal cancers            as angiodysplasia, inflammatory bowel
Author’s reply                                                                                        disease,      and      infective    colitis.
                                                   detected (4·3% in Glasgow vs 3·1% in
Sir—We strongly disagree with the                  Leeds). As the indications for                     Colonoscopy remains the standard for
statement that our review relies on self-          colonoscopy were similar, the most                 investigating the lower gastrointestinal
serving data from companies. Our                   likely reason for this difference is that          tract. Furthermore, patients undergoing
review was based on all available sources          patients in the study by Smith and                 colonoscopy        only     require     one
of information, including the sources              colleagues were on average 16 years                investigation for the examination of the
quoted by Sidney Wolfe and colleagues.             older (median age 77 years in Glasgow              colon rather than two (sigmoidoscopy
The sources quoted by Wolfe and                    vs 61 years in Leeds). In fact, no                 and barium enema). We believe that
colleagues did not provide us with any             patients below age 60 years were                   greater resources should be channelled
additional information that would have             investigated with colonoscopy in the               into colonoscopic services.
made us change any of the conclusions              series from Glasgow.
                                                                                                      *B J Rembacken, T Fujii, S Yoshida,
reached in our review.                                Paradoxically, although the patients
                                                                                                      D M Chalmers, A T R Axon
Johan Auwerx
                                                   in Leeds were almost two decades
                                                   younger, more adenomas were found in               *Centre for Digestive Diseases, The General
Institut de Genetique et Biologie Moleculaire et                                                      Infirmary at Leeds, Leeds LS16 8LT, UK; and
Cellulaire (IGBMC), 67404 Illkirch, France         this population. In their article, Smith           National Cancer Centre, Tokyo, Japan
(e-mail: auwerx@igbmc.u-strasbg.fr)                and colleagues do not elaborate on the             (e-mail: BJR@firstnet.co.uk)

THE LANCET • Vol 356 • July 15, 2000                                                                                                           255

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