- Email: [email protected]
Circumcision to prevent HPV infection
David Parker/Science Photo Library
Reflection and Reaction
There are worldwide shortages in the supply of medical isotopes
outage of several months in 2010. These two reactors supply nearly all of the Mo-99 used in North America. Retail vendors must look to the reactors in Belgium, France, and South Africa for supply. The only new source of Mo-99 is from a reactor in Australia, which is preparing to produce the radioisotope for the North American market but has not yet begun shipments. In the USA, two initiatives are underway to address the shortage of Mo-99. One plan is to use a research reactor at the University of Missouri to produce the radioisotope; however, a new facility is needed to process targets to separate the Mo-99, and it will likely be 2012 before the facility is operational. In the long term, Covidien, a company that produces Mo-99 at the reactor in the Netherlands, has partnered with the engineering firm Babcock and Wilcox to design and build a reactor with an aqueous core for medical isotope production. The advantage of this approach is that the fuel itself is the
source of Mo-99, rather than targets that are inserted into the system. Estimates range between 4 and 7 years for this technology to become operational. What do we do in the meantime? The Society of Nuclear Medicine has proposed several measures. First, use smaller doses and image the patients longer. Second, do imaging studies 7 days a week; Mo-99 decays into Tc-99m every day. Third, shift to other radiopharmaceuticals when possible. Thallium-201 was used in the past for cardiac imaging, which constitutes 40% of nuclear medicine studies, and is available from accelerators rather than reactors. Bone scans to stage patients with breast, prostate, and lung cancer can be done with F-18 sodium fluoride PET-CT, rather than Tc-99m phosphates. In Europe and Canada, authorities have approved this shift. The Society of Nuclear Medicine is working with the US Medicare system to approve reimbursement for this procedure. Many nuclear-medicine imaging studies are done to provide optimum information about the patient. Alternative imaging studies will result in some combination of higher radiation dose, less sensitivity or accuracy, higher cost, or more invasive procedures. We are working hard to identify the best short, medium, and long-term options to improve the availability and reliability of Mo-99 for the global market, and to ensure the best care for patients. But an aging infrastructure presents continuing challenges in securing a reliable supply of Mo-99. A combination of efforts by government, regulatory, commercial, and medical stakeholders is needed to successfully address this problem. Robert W Atcher Bioscience Division, University of New Mexico, Los Alamos National Laboratory, NM, USA [email protected] RWA is the immediate past president of the Society of Nuclear Medicine. The author declared no conflicts of interest.
Circumcision to prevent HPV infection We read with interest the recent editorial1 suggesting that male circumcision might prove an effective cancer-prevention strategy in developing nations where the vaccine for human papillomavirus (HPV) may not be readily available. Unfortunately, the editors’ exposition is based on a debatable premise: namely that HPV is less prevalent among circumcised 746
men. The editors cite a recently published study to support their claim; however, the positive results of this randomised trial,2 and one published previously,3 can be fully explained on the basis of sampling bias. Several studies have shown that the penile location from which HPV can be isolated differs by circumcision status.4–7 HPV is found primarily on the penile shaft in www.thelancet.com/oncology Vol 10 August 2009
Reflection and Reaction
circumcised men and on the glans in uncircumcised men. In a study in which multiple penile sites were sampled, 65% of uncircumcised men with HPV had the virus on the glans, whereas 48% of circumcised men with HPV had the virus on the glans.4 This study found that if only the glans is sampled, the risk of HPV in circumcised men is underestimated by 35%.4 Both of the randomised controlled trials sampled only the glans for HPV.3,4 If the numbers in study by Tobian and colleagues2 are adjusted for this sampling bias, the odds ratio becomes 0·83 (95% CI 0·56–1·24), which is no longer statistically significant. Likewise, if the numbers in the study by Auvert and colleagues3 are adjusted for sampling bias, the intention-to-treat odds ratio becomes 0·87 (0·66–1·14), again no longer statistically significant. If these studies had instead sampled only the penile shaft for HPV, they would likely have found circumcised men to be at greater risk for HPV infection. The effect of sampling bias has been consistent in the medical literature. A 2007 meta-analysis reviewed the effect of circumcision status on the presence of genital HPV and found that sampling only the glans and relying on patient report of circumcision status substantially affected a study’s odds ratio.8 When studies published subsequent to this meta-analysis are included,5–7 and adjustments are made using meta-regression9 for patient report of circumcision status and sampling only the glans (both of which were statistically significant confounding factors), the summary odds ratio is 0·89 (95% CI 0·72–1·10, p=0·28). This difference is not statistically significant. The effect of sampling bias is also evident when constructing a funnel graph, in which the x-axis is
the natural logarithm of the odds ratio and the y-axis represents the size of the study. The distribution of the points, which should look like an inverted funnel, is dominated on the left side by studies in which the penile shaft was not sampled—a clear demarcation confirming that a study’s odds ratio are differentially affected by incomplete sampling. With no strong evidence that circumcision affects HPV infection, the rest of the editorial becomes moot. Robert S Van Howe*, Michelle R Storms Department of Pediatrics and Human Development (RSVH) and Department of Family Medicine (MRS), Michigan State University College of Human Medicine, Marquette, MI, USA [email protected] The authors declared no conflicts of interest. 1 2
3
4
5
6
7
8 9
Male circumcision: a cancer prevention strategy [editorial]? Lancet Oncol 2009: 10: 431. Tobian AAR, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360: 1298–309. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of human-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis 2009; 199: 14–19. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis 2004; 189: 677–85. Hernandez BY, Wilkens LR, Zhu X, et al. Circumcision and human papillomavirus infection in men: a site-specific comparison. J Infect Dis 2008; 197: 787–94. Nielson CM, Schiaffino MK, Dunne EF, Salemi JL, Giuliano AR. Associations between male anogenital human papillomavirus infection and circumcision by anatomic site sampled and lifetime number of female sex partners. J Infect Dis 2009; 199: 7–13. Dickson NP, Ryding J, van Roode T, et al. Male circumcision and serologically determined human papillomavirus infection in a birth cohort. Cancer Epidemiol Biomarkers Prev 2009; 18: 177–83. Van Howe RS. Human papillomavirus and circumcision: a meta-analysis. J Infect 2007; 54: 490–96. Van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 2002; 21: 589–624.
Palliative sedation is not controversial In their interesting Personal View in the June issue of The Lancet Oncology, Materstvedt and Bosshard rightly consider the philosophical question of personhood as an ethical concern for continuous palliative sedation.1 However, their qualification of sedated patients as “living dead” seems highly problematic. The authors state that in the case of deep and continuous sedation, a patient´s social life is ended. Furthermore, they conclude that “in this regard, palliative sedation has an unclear border with euthanasia” and that a sedated www.thelancet.com/oncology Vol 10 August 2009
person has, in fact, been killed.1 First, although any sleep can be your last, no one will claim that a sleeping person is a living dead or a nonperson, even when it seems to be the individual’s last sleep. Descartes, in particular, acknowledged that sleeping and dreaming can be states in which thinking activity continues. Second, by contrast with dead people, sedated patients remain care receivers. As such, they have continued relationships with relatives and caregivers. This points to clear physical differences between states of 747
Reflection and Reaction
There are worldwide shortages in the supply of medical isotopes
outage of several months in 2010. These two reactors supply nearly all of the Mo-99 used in North America. Retail vendors must look to the reactors in Belgium, France, and South Africa for supply. The only new source of Mo-99 is from a reactor in Australia, which is preparing to produce the radioisotope for the North American market but has not yet begun shipments. In the USA, two initiatives are underway to address the shortage of Mo-99. One plan is to use a research reactor at the University of Missouri to produce the radioisotope; however, a new facility is needed to process targets to separate the Mo-99, and it will likely be 2012 before the facility is operational. In the long term, Covidien, a company that produces Mo-99 at the reactor in the Netherlands, has partnered with the engineering firm Babcock and Wilcox to design and build a reactor with an aqueous core for medical isotope production. The advantage of this approach is that the fuel itself is the
source of Mo-99, rather than targets that are inserted into the system. Estimates range between 4 and 7 years for this technology to become operational. What do we do in the meantime? The Society of Nuclear Medicine has proposed several measures. First, use smaller doses and image the patients longer. Second, do imaging studies 7 days a week; Mo-99 decays into Tc-99m every day. Third, shift to other radiopharmaceuticals when possible. Thallium-201 was used in the past for cardiac imaging, which constitutes 40% of nuclear medicine studies, and is available from accelerators rather than reactors. Bone scans to stage patients with breast, prostate, and lung cancer can be done with F-18 sodium fluoride PET-CT, rather than Tc-99m phosphates. In Europe and Canada, authorities have approved this shift. The Society of Nuclear Medicine is working with the US Medicare system to approve reimbursement for this procedure. Many nuclear-medicine imaging studies are done to provide optimum information about the patient. Alternative imaging studies will result in some combination of higher radiation dose, less sensitivity or accuracy, higher cost, or more invasive procedures. We are working hard to identify the best short, medium, and long-term options to improve the availability and reliability of Mo-99 for the global market, and to ensure the best care for patients. But an aging infrastructure presents continuing challenges in securing a reliable supply of Mo-99. A combination of efforts by government, regulatory, commercial, and medical stakeholders is needed to successfully address this problem. Robert W Atcher Bioscience Division, University of New Mexico, Los Alamos National Laboratory, NM, USA [email protected] RWA is the immediate past president of the Society of Nuclear Medicine. The author declared no conflicts of interest.
Circumcision to prevent HPV infection We read with interest the recent editorial1 suggesting that male circumcision might prove an effective cancer-prevention strategy in developing nations where the vaccine for human papillomavirus (HPV) may not be readily available. Unfortunately, the editors’ exposition is based on a debatable premise: namely that HPV is less prevalent among circumcised 746
men. The editors cite a recently published study to support their claim; however, the positive results of this randomised trial,2 and one published previously,3 can be fully explained on the basis of sampling bias. Several studies have shown that the penile location from which HPV can be isolated differs by circumcision status.4–7 HPV is found primarily on the penile shaft in www.thelancet.com/oncology Vol 10 August 2009
Reflection and Reaction
circumcised men and on the glans in uncircumcised men. In a study in which multiple penile sites were sampled, 65% of uncircumcised men with HPV had the virus on the glans, whereas 48% of circumcised men with HPV had the virus on the glans.4 This study found that if only the glans is sampled, the risk of HPV in circumcised men is underestimated by 35%.4 Both of the randomised controlled trials sampled only the glans for HPV.3,4 If the numbers in study by Tobian and colleagues2 are adjusted for this sampling bias, the odds ratio becomes 0·83 (95% CI 0·56–1·24), which is no longer statistically significant. Likewise, if the numbers in the study by Auvert and colleagues3 are adjusted for sampling bias, the intention-to-treat odds ratio becomes 0·87 (0·66–1·14), again no longer statistically significant. If these studies had instead sampled only the penile shaft for HPV, they would likely have found circumcised men to be at greater risk for HPV infection. The effect of sampling bias has been consistent in the medical literature. A 2007 meta-analysis reviewed the effect of circumcision status on the presence of genital HPV and found that sampling only the glans and relying on patient report of circumcision status substantially affected a study’s odds ratio.8 When studies published subsequent to this meta-analysis are included,5–7 and adjustments are made using meta-regression9 for patient report of circumcision status and sampling only the glans (both of which were statistically significant confounding factors), the summary odds ratio is 0·89 (95% CI 0·72–1·10, p=0·28). This difference is not statistically significant. The effect of sampling bias is also evident when constructing a funnel graph, in which the x-axis is
the natural logarithm of the odds ratio and the y-axis represents the size of the study. The distribution of the points, which should look like an inverted funnel, is dominated on the left side by studies in which the penile shaft was not sampled—a clear demarcation confirming that a study’s odds ratio are differentially affected by incomplete sampling. With no strong evidence that circumcision affects HPV infection, the rest of the editorial becomes moot. Robert S Van Howe*, Michelle R Storms Department of Pediatrics and Human Development (RSVH) and Department of Family Medicine (MRS), Michigan State University College of Human Medicine, Marquette, MI, USA [email protected] The authors declared no conflicts of interest. 1 2
3
4
5
6
7
8 9
Male circumcision: a cancer prevention strategy [editorial]? Lancet Oncol 2009: 10: 431. Tobian AAR, Serwadda D, Quinn TC, et al. Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 2009; 360: 1298–309. Auvert B, Sobngwi-Tambekou J, Cutler E, et al. Effect of male circumcision on the prevalence of human-risk human papillomavirus in young men: results of a randomized controlled trial conducted in Orange Farm, South Africa. J Infect Dis 2009; 199: 14–19. Weaver BA, Feng Q, Holmes KK, et al. Evaluation of genital sites and sampling techniques for detection of human papillomavirus DNA in men. J Infect Dis 2004; 189: 677–85. Hernandez BY, Wilkens LR, Zhu X, et al. Circumcision and human papillomavirus infection in men: a site-specific comparison. J Infect Dis 2008; 197: 787–94. Nielson CM, Schiaffino MK, Dunne EF, Salemi JL, Giuliano AR. Associations between male anogenital human papillomavirus infection and circumcision by anatomic site sampled and lifetime number of female sex partners. J Infect Dis 2009; 199: 7–13. Dickson NP, Ryding J, van Roode T, et al. Male circumcision and serologically determined human papillomavirus infection in a birth cohort. Cancer Epidemiol Biomarkers Prev 2009; 18: 177–83. Van Howe RS. Human papillomavirus and circumcision: a meta-analysis. J Infect 2007; 54: 490–96. Van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med 2002; 21: 589–624.
Palliative sedation is not controversial In their interesting Personal View in the June issue of The Lancet Oncology, Materstvedt and Bosshard rightly consider the philosophical question of personhood as an ethical concern for continuous palliative sedation.1 However, their qualification of sedated patients as “living dead” seems highly problematic. The authors state that in the case of deep and continuous sedation, a patient´s social life is ended. Furthermore, they conclude that “in this regard, palliative sedation has an unclear border with euthanasia” and that a sedated www.thelancet.com/oncology Vol 10 August 2009
person has, in fact, been killed.1 First, although any sleep can be your last, no one will claim that a sleeping person is a living dead or a nonperson, even when it seems to be the individual’s last sleep. Descartes, in particular, acknowledged that sleeping and dreaming can be states in which thinking activity continues. Second, by contrast with dead people, sedated patients remain care receivers. As such, they have continued relationships with relatives and caregivers. This points to clear physical differences between states of 747