- Email: [email protected]
Nipple fluid bFGF
CORRESPONDENCE
Authors’ reply
readily available, but only for patients with no alarm symptoms or signs.
Sir—The question of generalisability has to be carefully assessed in all clinical trials before they are implemented in clinical practice. Alberto Pilotto and co-workers question whether our results are applicable to dyspeptic patients aged 65 years and older for H pylori test and eradication to identify patients with peptic ulcer, gastric cancer, and oesophagitis. Pilotto and co-workers’ findings, however, relate to a selected subsample of dyspeptic patients who had been referred for investigation, and might have no relevance to management in primary care of unselected patients without alarm symptoms or signs. We included patients in primary care who had dyspepsia of a nature and severity that made the physician suggest treatment or investigation of any kind. We included 69 patients who were 65 years or older. The family physicians would have managed 43 (62%) of these patients by referral for endoscopy and would have treated 26 (38%) empirically had they not been referred for the trial. 42 patients were randomised for prompt endoscopy and can serve as a validation group for the H pylori test-and-eradicate strategy. 23 (55%) of 42 were H pylori positive, and eight of these patients had peptic ulcer, four had oesophagitis, one had cancer, and ten had normal endoscopy. Three of the six H pylori-negative patients who had used NSAIDs had peptic ulcer; the remaining three had a normal endoscopy. Four of the six H pylori-negative patients with reflux symptoms had oesophagitis; two had normal endoscopy. Five of the seven H pylori-negative patients without NSAID use or reflux symptoms had normal endoscopy, and two had mild oesophagitis. Thus, all patients with peptic ulcer (11 of 11) would have undergone endoscopy or been treated by eradication therapy, which suggests that the strategy is safe for management of such patients in this age-group. However, as previously stated, we have no power to judge the safety for identification of any gastric-cancer patients. We acknowledge the lack of data on the outcome for elderly patients from other clinical trials. Furthermore we doubt the value of post-trial planned subanalysis. However, based on our findings, we recommend the test-and-eradicate strategy as a safe alternative when endoscopy is not
*Annmarie Touborg Lassen, Finn Møller Pedersen, Peter Bytzer, Ove B Schaffalitzky de Muckadell
1684
Department of Medical Gastroenterology, Odense University Hospital, Odense DK-5000, Denmark (e-mail: [email protected])
Nipple fluid bFGF Sir—It seems inappropriate for Yeheng Liu and co-workers (Aug 12, p 567)1 to state that the control group had a mean concentration of nipple fluid bFGF of 19 ng/L (SD 19). Given that the limit of detection is stated to be 100 ng/L, it does not seem reasonable to assume that not detected corresponds to 0. Even if this dubious assumption is made then the SD in the control group would be 60 ng/L, not 19. If the same assumption is made for the breast-cancer group, the SD would be 2233·7 ng/L not 706. The values in the table also clearly show that comparing the two groups by t test is not appropriate. However, if it were correct, the corresponding p value would not be 0·027 by use of the means and SDs supplied. 706 given as the SD of the breast-cancer group seems to actually be the SE of the difference in the means. It is not obvious what is the appropriate statistical test to use given the data, but a randomisation test would seem to be useful here. A twosided test of this type gives p=0·000227. Statistical tests are, however, only useful as a first step in eliminating analyses that give no significant results. For example, if we were to use any detectable concentration of bFGF as indicating breast cancer, a diagnostic test would have sensitivity and specificity of 90%, each with a 95% CI of 55·50–99·75%. Such a diagnostic test might or might not be useful. I do hope that the above does not indicate that The Lancet feels that research letters should not be subjected to statistical refereeing. Alan C C Gibbs Christie Hospital NHS Trust, Kinnaird Road, Withington, Manchester M20 4QL, UK
Author’s reply Sir—The detection limit was 100 ng/L which allows assumptions of undetectable values to range from 0 to 99. We do not think that the assumption of any one number between 0 and 99 is more or less dubious than other.
Our numerical values were expressed with SE, not SD. We appreciate Alan Gibb’s analysis with the randomisation test, and are highly encouraged that his derived p value of 0·000227 is even more significant than our previously calculated p value of 0·027. The presented data are only preliminary. The ultimate significant value, if any, of this scientific observation will depend on the future validation by a larger clinical trial with numbers of patients, and not on the p value of the data derived from these few patients. Mai Nguyen Division of Surgical Oncology, University of California, CA 90095, USA
Hazards of multiple use of pharmaceutical solutions Sir—George Webster and colleagues (July 29, p 379)1 bring to light the risks of cross-contamination from use of injectable products in more than one patient. Two contemporary reports have involved cross-infection with Plasmodium falciparum malaria, probably from multiple use of vials of heparin and sodium chloride 0·9%, for flushing intravenous lines,2,3 and simulated studies have shown the possibility of cross-infection with multidose vials.4 Webster and colleagues’ example underscores the risks of receiving treatment in an unregulated setting. Additionally, however, it shows a lack of understanding of what is a multidose vial. The researchers refer to a multidose container of saline. All injectable presentations of normal saline in the UK are designed for single use only, even when they are presented in a sealed vial or bag that permits multiple dose removal. True multidose vials, in which antibacterial preservatives are present, are restricted to a few agents such as insulins and some heparin, lignocaine, and octreotide products. Although seldom stated in product information, to keep to a minimum the risk of cross-infection, multidose preparations should typically be restricted to use in one single patient, especially if the product is stored between uses for long periods. Antimicrobials used as preservatives are generally highly active against bacterial and fungal pathogens, but not against viruses and other infective agents such as protozoa and prions. Also, antimicrobial preservatives have reduced activity at low temperatures;
THE LANCET • Vol 356 • November 11, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Authors’ reply
readily available, but only for patients with no alarm symptoms or signs.
Sir—The question of generalisability has to be carefully assessed in all clinical trials before they are implemented in clinical practice. Alberto Pilotto and co-workers question whether our results are applicable to dyspeptic patients aged 65 years and older for H pylori test and eradication to identify patients with peptic ulcer, gastric cancer, and oesophagitis. Pilotto and co-workers’ findings, however, relate to a selected subsample of dyspeptic patients who had been referred for investigation, and might have no relevance to management in primary care of unselected patients without alarm symptoms or signs. We included patients in primary care who had dyspepsia of a nature and severity that made the physician suggest treatment or investigation of any kind. We included 69 patients who were 65 years or older. The family physicians would have managed 43 (62%) of these patients by referral for endoscopy and would have treated 26 (38%) empirically had they not been referred for the trial. 42 patients were randomised for prompt endoscopy and can serve as a validation group for the H pylori test-and-eradicate strategy. 23 (55%) of 42 were H pylori positive, and eight of these patients had peptic ulcer, four had oesophagitis, one had cancer, and ten had normal endoscopy. Three of the six H pylori-negative patients who had used NSAIDs had peptic ulcer; the remaining three had a normal endoscopy. Four of the six H pylori-negative patients with reflux symptoms had oesophagitis; two had normal endoscopy. Five of the seven H pylori-negative patients without NSAID use or reflux symptoms had normal endoscopy, and two had mild oesophagitis. Thus, all patients with peptic ulcer (11 of 11) would have undergone endoscopy or been treated by eradication therapy, which suggests that the strategy is safe for management of such patients in this age-group. However, as previously stated, we have no power to judge the safety for identification of any gastric-cancer patients. We acknowledge the lack of data on the outcome for elderly patients from other clinical trials. Furthermore we doubt the value of post-trial planned subanalysis. However, based on our findings, we recommend the test-and-eradicate strategy as a safe alternative when endoscopy is not
*Annmarie Touborg Lassen, Finn Møller Pedersen, Peter Bytzer, Ove B Schaffalitzky de Muckadell
1684
Department of Medical Gastroenterology, Odense University Hospital, Odense DK-5000, Denmark (e-mail: [email protected])
Nipple fluid bFGF Sir—It seems inappropriate for Yeheng Liu and co-workers (Aug 12, p 567)1 to state that the control group had a mean concentration of nipple fluid bFGF of 19 ng/L (SD 19). Given that the limit of detection is stated to be 100 ng/L, it does not seem reasonable to assume that not detected corresponds to 0. Even if this dubious assumption is made then the SD in the control group would be 60 ng/L, not 19. If the same assumption is made for the breast-cancer group, the SD would be 2233·7 ng/L not 706. The values in the table also clearly show that comparing the two groups by t test is not appropriate. However, if it were correct, the corresponding p value would not be 0·027 by use of the means and SDs supplied. 706 given as the SD of the breast-cancer group seems to actually be the SE of the difference in the means. It is not obvious what is the appropriate statistical test to use given the data, but a randomisation test would seem to be useful here. A twosided test of this type gives p=0·000227. Statistical tests are, however, only useful as a first step in eliminating analyses that give no significant results. For example, if we were to use any detectable concentration of bFGF as indicating breast cancer, a diagnostic test would have sensitivity and specificity of 90%, each with a 95% CI of 55·50–99·75%. Such a diagnostic test might or might not be useful. I do hope that the above does not indicate that The Lancet feels that research letters should not be subjected to statistical refereeing. Alan C C Gibbs Christie Hospital NHS Trust, Kinnaird Road, Withington, Manchester M20 4QL, UK
Author’s reply Sir—The detection limit was 100 ng/L which allows assumptions of undetectable values to range from 0 to 99. We do not think that the assumption of any one number between 0 and 99 is more or less dubious than other.
Our numerical values were expressed with SE, not SD. We appreciate Alan Gibb’s analysis with the randomisation test, and are highly encouraged that his derived p value of 0·000227 is even more significant than our previously calculated p value of 0·027. The presented data are only preliminary. The ultimate significant value, if any, of this scientific observation will depend on the future validation by a larger clinical trial with numbers of patients, and not on the p value of the data derived from these few patients. Mai Nguyen Division of Surgical Oncology, University of California, CA 90095, USA
Hazards of multiple use of pharmaceutical solutions Sir—George Webster and colleagues (July 29, p 379)1 bring to light the risks of cross-contamination from use of injectable products in more than one patient. Two contemporary reports have involved cross-infection with Plasmodium falciparum malaria, probably from multiple use of vials of heparin and sodium chloride 0·9%, for flushing intravenous lines,2,3 and simulated studies have shown the possibility of cross-infection with multidose vials.4 Webster and colleagues’ example underscores the risks of receiving treatment in an unregulated setting. Additionally, however, it shows a lack of understanding of what is a multidose vial. The researchers refer to a multidose container of saline. All injectable presentations of normal saline in the UK are designed for single use only, even when they are presented in a sealed vial or bag that permits multiple dose removal. True multidose vials, in which antibacterial preservatives are present, are restricted to a few agents such as insulins and some heparin, lignocaine, and octreotide products. Although seldom stated in product information, to keep to a minimum the risk of cross-infection, multidose preparations should typically be restricted to use in one single patient, especially if the product is stored between uses for long periods. Antimicrobials used as preservatives are generally highly active against bacterial and fungal pathogens, but not against viruses and other infective agents such as protozoa and prions. Also, antimicrobial preservatives have reduced activity at low temperatures;
THE LANCET • Vol 356 • November 11, 2000
For personal use only. Not to be reproduced without permission of The Lancet.