- Email: [email protected]
Anastrozole for ductal carcinoma in situ
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Measles-associated encephalitis in children with renal transplants: a predictable effect of waning herd immunity? Sir—We wish to report two cases of measles-associated encephalitis in children with renal transplants. Our patients, children aged 8 and 13 years, presented with seizures, myoclonic jerks, and hemiparesis, and MRI showed that they had similar thalamic abnormalities. Both patients needed ventilatory support and intensive care, because of progressive neurological deterioration, including the development of bulbar palsy in one child. Laboratory indices of cerebrospinal fluid were unremarkable and PCR tests for herpes simplex, varicella-zoster virus, enteroviruses, and other opportunistic agents were all negative. However, measles IgM was detected in the serum samples of both children and retrospective analysis of stored samples showed seroconversion to measles coincident with their neurological presentations. Evidence for active measles virus infection was sought, and measles RNA was detected in samples of saliva, plasma, nasopharyngeal aspirate, and urine of the first child. Each child had been non-specifically unwell before neurological presentation. One child had symptoms suggestive of a viral infection—including fever, conjunctivitis, coryza, and a transient rash—and the other child had isolated conjunctivitis. Both children had received a single dose of measles mumps and rubella (MMR) vaccine before transplantation, but since they were transplanted at about 2 years of age, they were unable to have a preschool booster dose. Uptake of the MMR vaccine in southeast London is among the lowest in the UK. At the end of the first quarter of 2003, only 61·4% of children aged 2 years in Lambeth, Southwark, and Lewisham had received a first dose of MMR vaccine. According to provisional data, there were 66 clinical cases of measles in the second quarter of 2003, 39 of which have been confirmed to date (personal communication, Donal O’Sullivan, South East London Health Protection Unit, UK). The reappearance of measles in the community poses a severe threat to vulnerable immunocompromised individuals, including recipients of transplants. Without a
832
substantial increase in the uptake of MMR vaccination, difficult challenges lie ahead. Measles is a notoriously infectious agent, and can be transmitted without simultaneous contact. Immunocompromised individuals may manifest only a non-specific illness without rash, which makes rapid diagnosis difficult and delays start of appropriate infectioncontrol measures. In this era of waning herd immunity, there is a need for renewed awareness of measles as a cause of non-specific, respiratory, or neurological symptoms in immunocompromised individuals. Special vigilance is needed in those individuals who have not had natural measles, are unvaccinated, or are only suboptimally protected after a single dose of vaccine. In view of our two cases, clinical colleagues should be alerted to the possibility of atypical presentations of measles in immunocompromised patients. I Michael Kidd, Caroline J Booth, Susan P A Rigden, C Y William Tong, *Eithne M E MacMahon Departments of *Infection (IMK, CYWT, EMEM) and Paediatric Nephrology (CJB, SPAR)), Guy’s and St Thomas’ Hospital, London SE1 7EH, UK; and Department of Infectious Diseases, Guy’s, King’s and St Thomas’ School of Medicine, King’s College London (CYWT, EMEM) (e-mail: [email protected])
Anastrozole for ductal carcinoma in situ Sir—We thank Hazel Thornton (May 31, p 1911)1 for her supportive statements about the IBIS II information leaflet and acknowledge her helpful comments during its development. We are cautiously confident that the time is right to move into prevention of breast cancer with the aromatase inhibitor anastrozole. The ATAC trial2 was designed to provide information on side-effects of the drug to inform any subsequent prevention study, and it provides an invaluable early warning source for any toxicities. There are more than 12 000 years of follow up on women taking anastrozole in the ATAC trial so far, and total exposure exceeds 730 000 years. We continue to monitor this information closely and have an open
policy about keeping women in our prevention studies fully informed about risks and benefits. For further details see http://www.ibis-trials.org. Thornton’s concerns are mostly focused on the sequellae of a screendetected diagnosis of ductal carcinoma in situ (DCIS). In some respects the ability to diagnose DCIS is the greatest achievement of breast screening. If left untreated, about half of these lesions would progress to cancer, most in less than 6 years,3,4 and all can be successfully dealt with by adequate treatment. There is still uncertainty about what constitutes adequate local treatment, and much remains to be done to delineate the various subtypes of DCIS and to ascertain the minimum adequate treatment for each. However, the case for hormonal treatment of oestrogen or progesterone receptorpositive DCIS is already strong and, accordingly, we have focused our attention on which hormonal treatment—tamoxifen or anastrozole— is best for this subgroup of patients. For IBIS II, women with DCIS have up to 6 months to decide about entry, so there is plenty of time for discussion and no rush to make this important decision. We agree that more information about DCIS should be made available to women involved in screening and would suggest the BACUP website as a source (http://www.cancerbacup.org. uk/info/dcis). Women who attend for breast screening should be aware that cancer could be detected and give their implicit consent by agreeing to be screened. Any diagnosis of breast cancer will come as a shock to most women, and the fact that it is an imminently treatable in-situ lesion should be a compensating source of reassurance. Cervical screening is so effective because of the ability to identify committed pre-invasion lesions. One can only wish that all breast cancers could be detected as in-situ lesions. *Jack Cuzick, Clare O’Neill, Tony Howell, John Forbes IBIS Coordinating Centre, Cancer Research UK, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK (e-mail: [email protected])
THE LANCET • Vol 362 • September 6, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
CORRESPONDENCE
1
2
3
4
Thornton H. Anastrozole as a preventive agent in breast cancer. Lancet 2003; 361: 1911–12. ATAC trialists group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of post-menopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 259: 2131–29. Page DL, Dupont WD, Rogers LW, et al. Continued local recurrence of carcinoma 15–25 years after diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer 1995; 78: 1197–200. Yen MF, Tabar L, Vitak B, et al. Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening. Eur J Cancer 2003; 39: 1746–54.
Traffic law enforcement and safety Sir—Donald Redelmeier and colleagues (June 28, p 2177),1 emphasise the well known fact that extensive traffic-law enforcement reduces the frequency of fatal motorvehicle crashes in countries with high rates of motor-vehicle use.2,3 However, crashes are also caused by other factors,4 including social, economic, and environmental factors. All such factors need to be controlled for in a study into traffic crashes; the results of a study that concentrates on a single factor being potentially less valid and possibly misleading. In view of this fact, Redelmeier and colleagues seem to have overlooked important variables in their analysis that could affect their outcome—eg, vehicle miles travelled, vehicle density (number of registered motor vehicles divided by length of roads), speed-limit regulations imposed, and economic factors (rate of unemployment, etc). An understanding of the effect of such factors on traffic safety should help in the design and implementation of strategies to reduce traffic crashes worldwide, increase our knowledge of the relations between these factors and traffic law enforcement on traffic safety, and result in suggestions for policy change. Despite this shortcoming, the study provides an important insight into a neglected area of study. The general deterrence model suggests that the effectiveness of a legal threat depends on the perceived certainty, severity, and speed of the punishment in the event of a violation of the law. Thus, the results of this study are particularly pertinent to countries in which the police force is underused with respect to the enforcement of traffic laws.
*E B R Desapriya, I Nobutada, H Guanghong
*Donald A Redelmeier, Robert J Tibshirani, Leonard Evans
*British Columbia Injury Research and Prevention Unit, Centre for Community Child Health Research, Vancouver, British Columbia V6H 3V4, Canada (EBRD, IN); Institute of Social Sciences, University of Tsokuba, Ibaraki, Japan (HG) (e-mail: [email protected])
*University of Toronto, Sunnybrook and Women’s Hospital G-151, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5 (DAR); Science Serving Society, Bloomfield Hills, MI, USA (LE); Department of Health Research and Policy, Stanford, CA, USA (RJT) (e-mail: [email protected])
1
2 3 4
Redelmeier DA, Tibshirani RJ, Evans L. Traffic law enforcement and risk of death from motor vehicle crashes: case-crossover study. Lancet 2003; 361: 2177–82. Shepherd JP. Criminal deterrence as a public health strategy. Lancet 2001; 358: 1717–22. Desapriya E, Nobutada I. The deterrence issue. Lancet 2002; 359: 982. Wagenaar AC. Effects of macroeconomic conditions on the incidence of motor vehicle accidents. Accident Anal Prev 1984; 16: 191–205.
Authors’ reply Sir—E Desapriya and colleagues note that crash rates are affected by social and other external determinants of health. We agree, and concur that such factors also affect many standard biological diseases. They emphasise that such factors should be controlled for in the assessment of the effectiveness of a single variable. Again we agree, and underscore our rationale of using the case crossover approach because doing so allows each driver to serve as their own control and eliminates all confounding from fixed individual factors. Desapriya and colleagues seem to overlook the fact that we also examined multiple controls from different years and months, and observed robust findings in every case, contrary to the claim that fluctuations in distances travelled, vehicle density, speed regulations, or employment rates might explain our findings. Furthermore, we examined 11 years separately and noted consistent results (despite the multiple economic and social changes over the interim). External factors are, therefore, unlikely to be major confounders in our analysis. Finally, the remarkable consistency across seasons of the year, days of the week, and hours of the day further indicate that the observed reduction in fatal crashes after the average traffic conviction is not an indication of transient external factors. Desapriya and co-workers are correct that ecological analyses are prone to the biases listed; hence, we did not use ecological analysis in our work. They are also correct in their assertion that testing our methods in other settings would be important because of the scientific strategy of replication, and that implementation of any safety programme depends on sensitivity to local culture, preferences, and politics.
Sir—We question the global importance of Donald Redelmeier and colleagues’ articlel and the accompanying Commentary,2 describing the importance of law enforcement in reducing fatal motor-vehicle crashes. Redelmeier and co-workers conclude that traffic-law enforcement effectively reduces the frequency of fatal motor vehicle crashes in countries with high rates of motor vehicle use. We do not know whether they meant to limit their results to industrialised countries, but we doubt their relevance to many developing countries, where low rates of motor vehicle use are nonetheless associated with high rates of mortality. Analyses like these, calling for law enforcement while ignoring local social context, are worrisome. Our research,3,4 for example, on pedestrian injuries in Mexico has shown that law enforcement raises the risk of pedestrian mortality. The reason for this seemingly paradoxical finding is that drivers in Mexico fear the law because trials are extremely complicated and corruption within the enforcement network pervasive. As a result, 90% of cases in which cars hit pedestrians are classified as hit and run. The problem is not the law itself but how it is administered. Given that road safety will be the focus of World Health Day in 2004,2 research on this theme must be inclusive. Closer attention should, hence, be paid to local variation in a globalised world. *Martha Hijar, James A Trostle *Instituto Nacional de Salud Publica, Cuernavaca, Morelos 62508, Mexico (MH); Trinity College, Hartford, CT, USA (JAT) (e-mail: [email protected]) 1
2
3
4
Redelmeier DA, Tibshirani RJ, Evans L. Traffic law enforcement and risk of death from motor vehicle crashes: case-crossover study. Lancet 2003; 361: 2177–82. McCarthy M. Health impacts of transport: convicted drivers. Lancet 2003; 361: 2168. Hijar M, Chu LD, Kraus JF. Crossnational comparison of injury mortality: Los Angeles County, California and Mexico City, Mexico. Int J Epidemiol 2000; 29: 715–21. Hijar M, Trostle J, Bronfman M. Pedestrian injuries in Mexico: a multi-method approach. Soc Sci Med. Published online April 8, 2003. DOI: 10.1016/S0277-9536 (03)00067-4.
THE LANCET • Vol 362 • September 6, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
833
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Measles-associated encephalitis in children with renal transplants: a predictable effect of waning herd immunity? Sir—We wish to report two cases of measles-associated encephalitis in children with renal transplants. Our patients, children aged 8 and 13 years, presented with seizures, myoclonic jerks, and hemiparesis, and MRI showed that they had similar thalamic abnormalities. Both patients needed ventilatory support and intensive care, because of progressive neurological deterioration, including the development of bulbar palsy in one child. Laboratory indices of cerebrospinal fluid were unremarkable and PCR tests for herpes simplex, varicella-zoster virus, enteroviruses, and other opportunistic agents were all negative. However, measles IgM was detected in the serum samples of both children and retrospective analysis of stored samples showed seroconversion to measles coincident with their neurological presentations. Evidence for active measles virus infection was sought, and measles RNA was detected in samples of saliva, plasma, nasopharyngeal aspirate, and urine of the first child. Each child had been non-specifically unwell before neurological presentation. One child had symptoms suggestive of a viral infection—including fever, conjunctivitis, coryza, and a transient rash—and the other child had isolated conjunctivitis. Both children had received a single dose of measles mumps and rubella (MMR) vaccine before transplantation, but since they were transplanted at about 2 years of age, they were unable to have a preschool booster dose. Uptake of the MMR vaccine in southeast London is among the lowest in the UK. At the end of the first quarter of 2003, only 61·4% of children aged 2 years in Lambeth, Southwark, and Lewisham had received a first dose of MMR vaccine. According to provisional data, there were 66 clinical cases of measles in the second quarter of 2003, 39 of which have been confirmed to date (personal communication, Donal O’Sullivan, South East London Health Protection Unit, UK). The reappearance of measles in the community poses a severe threat to vulnerable immunocompromised individuals, including recipients of transplants. Without a
832
substantial increase in the uptake of MMR vaccination, difficult challenges lie ahead. Measles is a notoriously infectious agent, and can be transmitted without simultaneous contact. Immunocompromised individuals may manifest only a non-specific illness without rash, which makes rapid diagnosis difficult and delays start of appropriate infectioncontrol measures. In this era of waning herd immunity, there is a need for renewed awareness of measles as a cause of non-specific, respiratory, or neurological symptoms in immunocompromised individuals. Special vigilance is needed in those individuals who have not had natural measles, are unvaccinated, or are only suboptimally protected after a single dose of vaccine. In view of our two cases, clinical colleagues should be alerted to the possibility of atypical presentations of measles in immunocompromised patients. I Michael Kidd, Caroline J Booth, Susan P A Rigden, C Y William Tong, *Eithne M E MacMahon Departments of *Infection (IMK, CYWT, EMEM) and Paediatric Nephrology (CJB, SPAR)), Guy’s and St Thomas’ Hospital, London SE1 7EH, UK; and Department of Infectious Diseases, Guy’s, King’s and St Thomas’ School of Medicine, King’s College London (CYWT, EMEM) (e-mail: [email protected])
Anastrozole for ductal carcinoma in situ Sir—We thank Hazel Thornton (May 31, p 1911)1 for her supportive statements about the IBIS II information leaflet and acknowledge her helpful comments during its development. We are cautiously confident that the time is right to move into prevention of breast cancer with the aromatase inhibitor anastrozole. The ATAC trial2 was designed to provide information on side-effects of the drug to inform any subsequent prevention study, and it provides an invaluable early warning source for any toxicities. There are more than 12 000 years of follow up on women taking anastrozole in the ATAC trial so far, and total exposure exceeds 730 000 years. We continue to monitor this information closely and have an open
policy about keeping women in our prevention studies fully informed about risks and benefits. For further details see http://www.ibis-trials.org. Thornton’s concerns are mostly focused on the sequellae of a screendetected diagnosis of ductal carcinoma in situ (DCIS). In some respects the ability to diagnose DCIS is the greatest achievement of breast screening. If left untreated, about half of these lesions would progress to cancer, most in less than 6 years,3,4 and all can be successfully dealt with by adequate treatment. There is still uncertainty about what constitutes adequate local treatment, and much remains to be done to delineate the various subtypes of DCIS and to ascertain the minimum adequate treatment for each. However, the case for hormonal treatment of oestrogen or progesterone receptorpositive DCIS is already strong and, accordingly, we have focused our attention on which hormonal treatment—tamoxifen or anastrozole— is best for this subgroup of patients. For IBIS II, women with DCIS have up to 6 months to decide about entry, so there is plenty of time for discussion and no rush to make this important decision. We agree that more information about DCIS should be made available to women involved in screening and would suggest the BACUP website as a source (http://www.cancerbacup.org. uk/info/dcis). Women who attend for breast screening should be aware that cancer could be detected and give their implicit consent by agreeing to be screened. Any diagnosis of breast cancer will come as a shock to most women, and the fact that it is an imminently treatable in-situ lesion should be a compensating source of reassurance. Cervical screening is so effective because of the ability to identify committed pre-invasion lesions. One can only wish that all breast cancers could be detected as in-situ lesions. *Jack Cuzick, Clare O’Neill, Tony Howell, John Forbes IBIS Coordinating Centre, Cancer Research UK, Wolfson Institute of Preventive Medicine, London EC1M 6BQ, UK (e-mail: [email protected])
THE LANCET • Vol 362 • September 6, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
CORRESPONDENCE
1
2
3
4
Thornton H. Anastrozole as a preventive agent in breast cancer. Lancet 2003; 361: 1911–12. ATAC trialists group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of post-menopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 259: 2131–29. Page DL, Dupont WD, Rogers LW, et al. Continued local recurrence of carcinoma 15–25 years after diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer 1995; 78: 1197–200. Yen MF, Tabar L, Vitak B, et al. Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening. Eur J Cancer 2003; 39: 1746–54.
Traffic law enforcement and safety Sir—Donald Redelmeier and colleagues (June 28, p 2177),1 emphasise the well known fact that extensive traffic-law enforcement reduces the frequency of fatal motorvehicle crashes in countries with high rates of motor-vehicle use.2,3 However, crashes are also caused by other factors,4 including social, economic, and environmental factors. All such factors need to be controlled for in a study into traffic crashes; the results of a study that concentrates on a single factor being potentially less valid and possibly misleading. In view of this fact, Redelmeier and colleagues seem to have overlooked important variables in their analysis that could affect their outcome—eg, vehicle miles travelled, vehicle density (number of registered motor vehicles divided by length of roads), speed-limit regulations imposed, and economic factors (rate of unemployment, etc). An understanding of the effect of such factors on traffic safety should help in the design and implementation of strategies to reduce traffic crashes worldwide, increase our knowledge of the relations between these factors and traffic law enforcement on traffic safety, and result in suggestions for policy change. Despite this shortcoming, the study provides an important insight into a neglected area of study. The general deterrence model suggests that the effectiveness of a legal threat depends on the perceived certainty, severity, and speed of the punishment in the event of a violation of the law. Thus, the results of this study are particularly pertinent to countries in which the police force is underused with respect to the enforcement of traffic laws.
*E B R Desapriya, I Nobutada, H Guanghong
*Donald A Redelmeier, Robert J Tibshirani, Leonard Evans
*British Columbia Injury Research and Prevention Unit, Centre for Community Child Health Research, Vancouver, British Columbia V6H 3V4, Canada (EBRD, IN); Institute of Social Sciences, University of Tsokuba, Ibaraki, Japan (HG) (e-mail: [email protected])
*University of Toronto, Sunnybrook and Women’s Hospital G-151, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5 (DAR); Science Serving Society, Bloomfield Hills, MI, USA (LE); Department of Health Research and Policy, Stanford, CA, USA (RJT) (e-mail: [email protected])
1
2 3 4
Redelmeier DA, Tibshirani RJ, Evans L. Traffic law enforcement and risk of death from motor vehicle crashes: case-crossover study. Lancet 2003; 361: 2177–82. Shepherd JP. Criminal deterrence as a public health strategy. Lancet 2001; 358: 1717–22. Desapriya E, Nobutada I. The deterrence issue. Lancet 2002; 359: 982. Wagenaar AC. Effects of macroeconomic conditions on the incidence of motor vehicle accidents. Accident Anal Prev 1984; 16: 191–205.
Authors’ reply Sir—E Desapriya and colleagues note that crash rates are affected by social and other external determinants of health. We agree, and concur that such factors also affect many standard biological diseases. They emphasise that such factors should be controlled for in the assessment of the effectiveness of a single variable. Again we agree, and underscore our rationale of using the case crossover approach because doing so allows each driver to serve as their own control and eliminates all confounding from fixed individual factors. Desapriya and colleagues seem to overlook the fact that we also examined multiple controls from different years and months, and observed robust findings in every case, contrary to the claim that fluctuations in distances travelled, vehicle density, speed regulations, or employment rates might explain our findings. Furthermore, we examined 11 years separately and noted consistent results (despite the multiple economic and social changes over the interim). External factors are, therefore, unlikely to be major confounders in our analysis. Finally, the remarkable consistency across seasons of the year, days of the week, and hours of the day further indicate that the observed reduction in fatal crashes after the average traffic conviction is not an indication of transient external factors. Desapriya and co-workers are correct that ecological analyses are prone to the biases listed; hence, we did not use ecological analysis in our work. They are also correct in their assertion that testing our methods in other settings would be important because of the scientific strategy of replication, and that implementation of any safety programme depends on sensitivity to local culture, preferences, and politics.
Sir—We question the global importance of Donald Redelmeier and colleagues’ articlel and the accompanying Commentary,2 describing the importance of law enforcement in reducing fatal motor-vehicle crashes. Redelmeier and co-workers conclude that traffic-law enforcement effectively reduces the frequency of fatal motor vehicle crashes in countries with high rates of motor vehicle use. We do not know whether they meant to limit their results to industrialised countries, but we doubt their relevance to many developing countries, where low rates of motor vehicle use are nonetheless associated with high rates of mortality. Analyses like these, calling for law enforcement while ignoring local social context, are worrisome. Our research,3,4 for example, on pedestrian injuries in Mexico has shown that law enforcement raises the risk of pedestrian mortality. The reason for this seemingly paradoxical finding is that drivers in Mexico fear the law because trials are extremely complicated and corruption within the enforcement network pervasive. As a result, 90% of cases in which cars hit pedestrians are classified as hit and run. The problem is not the law itself but how it is administered. Given that road safety will be the focus of World Health Day in 2004,2 research on this theme must be inclusive. Closer attention should, hence, be paid to local variation in a globalised world. *Martha Hijar, James A Trostle *Instituto Nacional de Salud Publica, Cuernavaca, Morelos 62508, Mexico (MH); Trinity College, Hartford, CT, USA (JAT) (e-mail: [email protected]) 1
2
3
4
Redelmeier DA, Tibshirani RJ, Evans L. Traffic law enforcement and risk of death from motor vehicle crashes: case-crossover study. Lancet 2003; 361: 2177–82. McCarthy M. Health impacts of transport: convicted drivers. Lancet 2003; 361: 2168. Hijar M, Chu LD, Kraus JF. Crossnational comparison of injury mortality: Los Angeles County, California and Mexico City, Mexico. Int J Epidemiol 2000; 29: 715–21. Hijar M, Trostle J, Bronfman M. Pedestrian injuries in Mexico: a multi-method approach. Soc Sci Med. Published online April 8, 2003. DOI: 10.1016/S0277-9536 (03)00067-4.
THE LANCET • Vol 362 • September 6, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
833