- Email: [email protected]
Breast cancer gets the hard sell
THE LANCET
We believe that our experience may inform future strategies for control and prevention of such occurrences. *Vijay R Battu, Patrick J Horner, Patrick K Taylor, Anthony E Jephcott, Stan I Egglestone *Milne Centre, Bristol Royal Infirmary, Bristol BS2 8HW, UK; and Public Health Laboratory, Bristol 1
2 3
4
Tichonova L, Borisenko K, Ward H, Meheus A, Gromyko A, Renton A. Epidemics of syphilis in the Russian Federation: trends, origins, and priorities for control. Lancet 1997; 350: 210–13. Department of Health. Sexually transmitted diseases, England 1995. Stat Bull 1996: 14. Sherrard J, Luzzi G, Edwards A. Imported syphilis and sexually transmitted infections among UK travellers to Russia and Poland. Genitourin Med 1997; 73: 75. Anon. An outbreak of infectious syphilis in Bristol. Commun Dis Rep 1997; 7: 291.
p53 involvement in BRCA1associated breast cancer SIR—The work of Tim Crook and colleagues (Aug 30, p 638),1 raises the important issue of a role for p53BRCA1 in the development of hereditary breast cancer. They postulate that p53 mutation is required, and say that “loss of such a checkpoint may be obligatory for BRCA1 tumorigenesis”. Even if this work is the first to report point mutations, the pivotal role of p53 has been suggested by two studies in which a high frequency of p53 overexpression was found in BRCA1associated breast cancers: 40%2 to 70%3 of such tumours were associated with positive p53 immunostaining. These results are not equivalent to the 100% mutations reported by Crook. Indeed, it is generally agreed that a large overlap exists between the presence of a mutation at the DNA level and positive immunostaining in breast cancer,4 implying that a high proportion of, but probably not all, BRCA1-associated breast cancers harbour a p53 mutation. Crook and colleagues go on to suggest that p53 mutation is responsible for the increased mitosis in BRCA1associated breast cancers. Actually, since not all such cancers are associated with p53 staining. BRCA1-germline mutation may, per se, affect the histoprognostic grade in hereditary breast cancer. Indeed, as shown from our data (see table), when comparing BRCA1-associated disease and sporadic cases, tumour proliferation is not solely under p53 control, but is also affected by the BRCA1-germline mutation (p=0·0007). It should also be noted that, despite a frequency of p53
Vol 350 • October 11, 1997
Tumours (all p53 positive)
BRCA1 cancers (n=29) Sporadic cases (n=200)
Mitotic index 1 and 2 (n=24)
3 (n=34)
0 24
12 22
Total
12 46
Two-sided Fisher’s exact statistical test used to compare groups, p=0·0007.
Proliferation rate in tumours with p53 mutation according to p53 germline status
positivity equivalent to those of BRCA1 cancers (70%), only 46% of hereditary non-BRCA1 breast cancers are associated with a high proliferation rate versus 77% in BRCA1-associated breast cancer (p=0·004).3 It seems that p53 involvement is more of an additional event than a mandatory checkpoint in hereditary breast carcinogenesis. There are two aspects that Crook and co-workers do not address. First, since different germline mutations may have various clinical and morphological effects, the determinations of the BRCA1-mutation spectrum associated with p53 alterations should be considered. In this respect, splice variants, which correspond to only 8% of reported BRCA1-disease-associated mutations (most lying in the ring finger region), were found in 50% of families analysed in this study. Interestingly, in a preliminary analysis, p53-positive staining was seen more consistently in tumours with mutation in the ring finger region of BRCA1 than that leading to a truncation of the BRCA1 C-terminus domain, which is believed to interact with p53.2 Second, it is important for future management to analyse the complex relations between p53 alterations and prognosis of BRCA1-associated breast cancers. As an example, medullary carcinoma of the breast, an excess of which is found among BRCA1associated disease, frequently harbour a genomic alteration of p53 (mainly in exon 5)5 but is usually regarded as having a better prognosis than other grade-3 ductal carcinomas. We thank Dominique Stoppa-Lyonnet, Brigitte Bressac-de Paillerets, Jean-Philippe Peyrat, and Philippe Vennin for their valuable contribution to this work.
François Eisinger, Jocelyne Jacquemier, Jean-Marc Guinebretiere, Daniel Birnbaum, *Hagay Sobol Departments of Prevention and Pathology, INSERM CRI 9703, Marseille; Department of Pathology, Gustave Roussy Institute, Villejuif; INSERM Unit 119, and Laboratory of Tumour Biology, Paoli-Calmettes Institute, Marseille; and *Department of Genetic Oncology and Laboratory of Tumour Biology, INSERM CRI 9703, Paoli-Calmettes Institute, 13272 Marseille, France e-mail: [email protected]
1
2
3
4
5
Crook T, Crossland S, Crompton M, Osin P, Gusterson B. p53 mutations in BRCA1-associated familial breast cancer. Lancet 1997; 350: 638–39. Sobol H, Stoppa-Lyonnet D, Bressac-de Paillerets B, et al. BRCA1-p53 relationships in hereditary breast cancer. Int J Oncol 1997; 10: 349–53. Johannson O, Idvall I, Anderson C, et al. Tumor biological features of BRCA1induced breast and ovarian cancer. Eur J Cancer 1997; 33: 362–71. Soussi T, Legros Y, Lubin R, Ory K, Schlichtholz B. Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 1994; 57: 1–9. Marchetti A, Buttitia F, Pellegrini S, et al. p53 mutations and histological type of massive breast carcinoma. Cancer Res 1993; 53: 4665–69.
Breast cancer gets the hard sell SIR—I wish to correct certain basic facts and, by inference, incorrect conclusions which might have been reached by readers of your August 9 editorial.1 On Aug 13, 1997, President Clinton signed the Stamp Out Breast Cancer Act. The bill, which had passed the House by a vote of 422 to 3, passed in the Senate by unanimous consent. The legislation instructs the US Postal Service to create and make available for voluntary purchase a stamp that will carry a surcharge of 1–8 cents. After covering the administrative costs of the postal service, the balance of funds raised will be used for breast cancer research. Contrary to the point made in the editorial, the money raised will be to fund research in the areas of diagnosis and treatment, as well as to fund projects targeted at finding the cure for this widespread cancer. As the editorial correctly states, we must take advantage of an opportunity to find better ways to diagnose and treat breast cancer and not just commit our resources to finding a cause. Another important part of the legislation that you overlook is the evaluation component which, if necessary, creates an automatic sunset provision. Although I agree with you that “the money will pour in”, if this approach does not raise sufficient funds, then, unlike so many other congressional mandates, it should not be with us forever. The way we make progress, irrespective of the area, is to try new approaches to problem solving. That is exactly what we are doing with this legislation. In answer to your concern about why the legislation is for breast cancer alone, I hope that your readers will realise that one of the basic ideas behind this legislation is to evaluate this method of raising funds. We feel strongly that it
1101
THE LANCET
will prove to be effective, and when that happens this approach can and will be used for various causes. By limiting the initial programme to just one cause, it is far easier to control and evaluate. For example, when special cause licence plates were first introduced, at least in California where I live, they were for environmental preservation only. Once that method of fund raising was proven successful, it was expanded and special licence plates are now available for many causes. This approach is certainly true in the private sector. A new consumer product is invariably introduced in just one form; if it is successful, we then find our supermarket shelves stocked with various line extensions of the product. Breast cancer was chosen for this project because it is of special interest to the three people who made this happen. One of us is a surgeon who is committed to finding better ways to care for his patients, the second is a 30year-old survivor of breast cancer who was given 2 years to live when she was diagnosed with the disease 5 years ago, and the third is myself, someone who lost his wife to breast cancer this year and who does not want to see his daughter, and millions of other young women like her, face the prospect of going through what her mother did. David L Goodman 2 Duncan Court, Orinda, CA 94563, USA 1
Editorial. Breast cancer gets the hard sell. Lancet 1997; 350: 377.
SIR—2·6 million women have breast cancer in the USA and another 1·6 million do not know they have the disease. Worldwide, every 30 s a new diagnosis is made, and every 3 min another woman dies. For the past 15 years, I have been personally responsible for devastating the lives of thousands of women and their loved ones. I have maimed, deformed, and defaced these women. I have robbed many of their sexuality, sent them into a state of deep depression, induced premature menopause, and accompanied hundreds to the grave. Yet I have no answers for any of my patients or their family members. The truth remains we still do not know what causes breast cancer, or how to cure it. I agree with your editorial1 that comforting breast cancer patients is important. But the only comfort they will receive is to know that attempts are being made to curb this fatal disease. For this reason, almost 2 years ago, I began a campaign to urge the US postal service to issue a voluntary 33-cent stamp—the additional cent directed towards cancer research.
1102
Last year alone the National Institute of Health was only able to fund 26% of the funding requests for breast cancer research. Any funds derived from the optional stamp would help to make advances in our management of the disease, and may also have a correlative effect on the management of other cancers. Breast cancer is undeniably a formidable disease and one in which very little progress has been realised in the past few years. Prevention is the key to breast cancer, and I cannot help but think that additional funds for research directed towards breast cancer may some day lead to a cure. The US Congress and President Clinton took the first step towards prevention when they signed the breast cancer research bill into law. Now it is up to the US public to buy the stamp and contribute to a cure for breast cancer. Ernie Bodai
(Gambia), and another study in the Philippines had rates of 95–100%.* The reasons for Milne’s results remain unclear; they could relate to the vaccine lot, difficulties with vaccine storage or delivery, or some specific characteristics of the Solomon Islands’ population. We have found no reason, at this time, to modify WHO advice that Cheil plasma-derived HB vaccine is acceptable in principle, nor to question the use of 1·5 mg doses of the vaccine among infants in schedules of 6, 10, and 14 weeks. *Full details and references available from The Lancet or the authors, on request.
*Mark Kane, Julie Milstien Global Programme for Vaccines and Immunization, *Expanded Programme on Immunization, World Health Organization, CH-1211 Geneva, Switzerland 1
Milne A, Rodgers E, Hopkirk N. Hepatitis B vaccination in babies in Melanesia. Lancet 1995; 346: 318.
Kaiser Permanente Medical Group, Sacramento, CA, USA 1
Editorial. Breast cancer gets the hard sell. Lancet 1997; 350: 377.
Immunogenicity of low-dose plasma-derived hepatitis B vaccine SIR—During the past year, concern has been expressed in several countries about the immunogenicity of plasmaderived hepatitis B (HB) vaccine manufactured by a South Korean company (Cheil Jedang) and supplied at a 1·5 mg dose for neonates. The basis for this concern stems from studies by A Milne and colleagues1 in the Solomon Islands, in which results obtained from Cheil plasma-derived vaccine were compared with those from a DNA recombinant HB vaccine. Seroconversion to the Cheil vaccine was 58% versus 88% for the recombinant HB vaccine. These results were widely distributed by competing manufacturers of HB vaccines before their publication. Since this vaccine has been assessed by WHO and found acceptable in principle for purchase by United Nations agencies, we decided to collect data on this vaccine from several countries to see if there were difficulties with the immunogenicity under field conditions in developing countries. Our findings indicate that the poor seroconversion reported by Milne in the Solomon Islands was not found in several other studies, most conducted in developing countries. Various rates of sercoversion have been reported at meetings, the lowest being 83% (Philippines), but the range in others was from 93% (South Africa) to 100%
EUCLID study SIR—The June 21 commentary by Ping Wang1 on whether angiotensinconverting-enzyme (ACE) inhibitors should be given to normotensive patients who have insulin-dependent diabetes (IDDM), the EUCLID study group report (June 21, p 1787),2 and Gerjan Navis and colleagues’ June 28 commentary3 raise some interesting issues. The conclusion of the EUCLID group that “lisinopril shows that progressions of renal disease in normotensive IDDM patients with little or no albuminuria” is not convincing. Their conclusion is probably based on the significant reduction in the albumin excretion rate after lisinopril treatment in these patients who had microalbuminuria. However, delayed progression of renal disease means a change in the glomerular filtration rate (GFR), and that indice was not measured. By contrast, the GISEN group (June 25, p 1857)4 examined the effect of ramipril on decline in GFR and risk of terminal renal failure in protienuric non-diabetic nephropathy and found that “in multivariate analysis, as expected, a lower baseline GFR was significantly associated with an increased risk of reaching an endpoint in the longterm (p=0·0001)”. Thus, the message is clear that the use of ACE inhibitors benefits deterioration of GFR, independently of reduction of protienuria or not. A guideline should be decided for those patients who have massive protienuria, rapid decline in GFR, and are heading towards endstage renal disease with multiple complications. The comment by Navis
Vol 350 • October 11, 1997
We believe that our experience may inform future strategies for control and prevention of such occurrences. *Vijay R Battu, Patrick J Horner, Patrick K Taylor, Anthony E Jephcott, Stan I Egglestone *Milne Centre, Bristol Royal Infirmary, Bristol BS2 8HW, UK; and Public Health Laboratory, Bristol 1
2 3
4
Tichonova L, Borisenko K, Ward H, Meheus A, Gromyko A, Renton A. Epidemics of syphilis in the Russian Federation: trends, origins, and priorities for control. Lancet 1997; 350: 210–13. Department of Health. Sexually transmitted diseases, England 1995. Stat Bull 1996: 14. Sherrard J, Luzzi G, Edwards A. Imported syphilis and sexually transmitted infections among UK travellers to Russia and Poland. Genitourin Med 1997; 73: 75. Anon. An outbreak of infectious syphilis in Bristol. Commun Dis Rep 1997; 7: 291.
p53 involvement in BRCA1associated breast cancer SIR—The work of Tim Crook and colleagues (Aug 30, p 638),1 raises the important issue of a role for p53BRCA1 in the development of hereditary breast cancer. They postulate that p53 mutation is required, and say that “loss of such a checkpoint may be obligatory for BRCA1 tumorigenesis”. Even if this work is the first to report point mutations, the pivotal role of p53 has been suggested by two studies in which a high frequency of p53 overexpression was found in BRCA1associated breast cancers: 40%2 to 70%3 of such tumours were associated with positive p53 immunostaining. These results are not equivalent to the 100% mutations reported by Crook. Indeed, it is generally agreed that a large overlap exists between the presence of a mutation at the DNA level and positive immunostaining in breast cancer,4 implying that a high proportion of, but probably not all, BRCA1-associated breast cancers harbour a p53 mutation. Crook and colleagues go on to suggest that p53 mutation is responsible for the increased mitosis in BRCA1associated breast cancers. Actually, since not all such cancers are associated with p53 staining. BRCA1-germline mutation may, per se, affect the histoprognostic grade in hereditary breast cancer. Indeed, as shown from our data (see table), when comparing BRCA1-associated disease and sporadic cases, tumour proliferation is not solely under p53 control, but is also affected by the BRCA1-germline mutation (p=0·0007). It should also be noted that, despite a frequency of p53
Vol 350 • October 11, 1997
Tumours (all p53 positive)
BRCA1 cancers (n=29) Sporadic cases (n=200)
Mitotic index 1 and 2 (n=24)
3 (n=34)
0 24
12 22
Total
12 46
Two-sided Fisher’s exact statistical test used to compare groups, p=0·0007.
Proliferation rate in tumours with p53 mutation according to p53 germline status
positivity equivalent to those of BRCA1 cancers (70%), only 46% of hereditary non-BRCA1 breast cancers are associated with a high proliferation rate versus 77% in BRCA1-associated breast cancer (p=0·004).3 It seems that p53 involvement is more of an additional event than a mandatory checkpoint in hereditary breast carcinogenesis. There are two aspects that Crook and co-workers do not address. First, since different germline mutations may have various clinical and morphological effects, the determinations of the BRCA1-mutation spectrum associated with p53 alterations should be considered. In this respect, splice variants, which correspond to only 8% of reported BRCA1-disease-associated mutations (most lying in the ring finger region), were found in 50% of families analysed in this study. Interestingly, in a preliminary analysis, p53-positive staining was seen more consistently in tumours with mutation in the ring finger region of BRCA1 than that leading to a truncation of the BRCA1 C-terminus domain, which is believed to interact with p53.2 Second, it is important for future management to analyse the complex relations between p53 alterations and prognosis of BRCA1-associated breast cancers. As an example, medullary carcinoma of the breast, an excess of which is found among BRCA1associated disease, frequently harbour a genomic alteration of p53 (mainly in exon 5)5 but is usually regarded as having a better prognosis than other grade-3 ductal carcinomas. We thank Dominique Stoppa-Lyonnet, Brigitte Bressac-de Paillerets, Jean-Philippe Peyrat, and Philippe Vennin for their valuable contribution to this work.
François Eisinger, Jocelyne Jacquemier, Jean-Marc Guinebretiere, Daniel Birnbaum, *Hagay Sobol Departments of Prevention and Pathology, INSERM CRI 9703, Marseille; Department of Pathology, Gustave Roussy Institute, Villejuif; INSERM Unit 119, and Laboratory of Tumour Biology, Paoli-Calmettes Institute, Marseille; and *Department of Genetic Oncology and Laboratory of Tumour Biology, INSERM CRI 9703, Paoli-Calmettes Institute, 13272 Marseille, France e-mail: [email protected]
1
2
3
4
5
Crook T, Crossland S, Crompton M, Osin P, Gusterson B. p53 mutations in BRCA1-associated familial breast cancer. Lancet 1997; 350: 638–39. Sobol H, Stoppa-Lyonnet D, Bressac-de Paillerets B, et al. BRCA1-p53 relationships in hereditary breast cancer. Int J Oncol 1997; 10: 349–53. Johannson O, Idvall I, Anderson C, et al. Tumor biological features of BRCA1induced breast and ovarian cancer. Eur J Cancer 1997; 33: 362–71. Soussi T, Legros Y, Lubin R, Ory K, Schlichtholz B. Multifactorial analysis of p53 alteration in human cancer: a review. Int J Cancer 1994; 57: 1–9. Marchetti A, Buttitia F, Pellegrini S, et al. p53 mutations and histological type of massive breast carcinoma. Cancer Res 1993; 53: 4665–69.
Breast cancer gets the hard sell SIR—I wish to correct certain basic facts and, by inference, incorrect conclusions which might have been reached by readers of your August 9 editorial.1 On Aug 13, 1997, President Clinton signed the Stamp Out Breast Cancer Act. The bill, which had passed the House by a vote of 422 to 3, passed in the Senate by unanimous consent. The legislation instructs the US Postal Service to create and make available for voluntary purchase a stamp that will carry a surcharge of 1–8 cents. After covering the administrative costs of the postal service, the balance of funds raised will be used for breast cancer research. Contrary to the point made in the editorial, the money raised will be to fund research in the areas of diagnosis and treatment, as well as to fund projects targeted at finding the cure for this widespread cancer. As the editorial correctly states, we must take advantage of an opportunity to find better ways to diagnose and treat breast cancer and not just commit our resources to finding a cause. Another important part of the legislation that you overlook is the evaluation component which, if necessary, creates an automatic sunset provision. Although I agree with you that “the money will pour in”, if this approach does not raise sufficient funds, then, unlike so many other congressional mandates, it should not be with us forever. The way we make progress, irrespective of the area, is to try new approaches to problem solving. That is exactly what we are doing with this legislation. In answer to your concern about why the legislation is for breast cancer alone, I hope that your readers will realise that one of the basic ideas behind this legislation is to evaluate this method of raising funds. We feel strongly that it
1101
THE LANCET
will prove to be effective, and when that happens this approach can and will be used for various causes. By limiting the initial programme to just one cause, it is far easier to control and evaluate. For example, when special cause licence plates were first introduced, at least in California where I live, they were for environmental preservation only. Once that method of fund raising was proven successful, it was expanded and special licence plates are now available for many causes. This approach is certainly true in the private sector. A new consumer product is invariably introduced in just one form; if it is successful, we then find our supermarket shelves stocked with various line extensions of the product. Breast cancer was chosen for this project because it is of special interest to the three people who made this happen. One of us is a surgeon who is committed to finding better ways to care for his patients, the second is a 30year-old survivor of breast cancer who was given 2 years to live when she was diagnosed with the disease 5 years ago, and the third is myself, someone who lost his wife to breast cancer this year and who does not want to see his daughter, and millions of other young women like her, face the prospect of going through what her mother did. David L Goodman 2 Duncan Court, Orinda, CA 94563, USA 1
Editorial. Breast cancer gets the hard sell. Lancet 1997; 350: 377.
SIR—2·6 million women have breast cancer in the USA and another 1·6 million do not know they have the disease. Worldwide, every 30 s a new diagnosis is made, and every 3 min another woman dies. For the past 15 years, I have been personally responsible for devastating the lives of thousands of women and their loved ones. I have maimed, deformed, and defaced these women. I have robbed many of their sexuality, sent them into a state of deep depression, induced premature menopause, and accompanied hundreds to the grave. Yet I have no answers for any of my patients or their family members. The truth remains we still do not know what causes breast cancer, or how to cure it. I agree with your editorial1 that comforting breast cancer patients is important. But the only comfort they will receive is to know that attempts are being made to curb this fatal disease. For this reason, almost 2 years ago, I began a campaign to urge the US postal service to issue a voluntary 33-cent stamp—the additional cent directed towards cancer research.
1102
Last year alone the National Institute of Health was only able to fund 26% of the funding requests for breast cancer research. Any funds derived from the optional stamp would help to make advances in our management of the disease, and may also have a correlative effect on the management of other cancers. Breast cancer is undeniably a formidable disease and one in which very little progress has been realised in the past few years. Prevention is the key to breast cancer, and I cannot help but think that additional funds for research directed towards breast cancer may some day lead to a cure. The US Congress and President Clinton took the first step towards prevention when they signed the breast cancer research bill into law. Now it is up to the US public to buy the stamp and contribute to a cure for breast cancer. Ernie Bodai
(Gambia), and another study in the Philippines had rates of 95–100%.* The reasons for Milne’s results remain unclear; they could relate to the vaccine lot, difficulties with vaccine storage or delivery, or some specific characteristics of the Solomon Islands’ population. We have found no reason, at this time, to modify WHO advice that Cheil plasma-derived HB vaccine is acceptable in principle, nor to question the use of 1·5 mg doses of the vaccine among infants in schedules of 6, 10, and 14 weeks. *Full details and references available from The Lancet or the authors, on request.
*Mark Kane, Julie Milstien Global Programme for Vaccines and Immunization, *Expanded Programme on Immunization, World Health Organization, CH-1211 Geneva, Switzerland 1
Milne A, Rodgers E, Hopkirk N. Hepatitis B vaccination in babies in Melanesia. Lancet 1995; 346: 318.
Kaiser Permanente Medical Group, Sacramento, CA, USA 1
Editorial. Breast cancer gets the hard sell. Lancet 1997; 350: 377.
Immunogenicity of low-dose plasma-derived hepatitis B vaccine SIR—During the past year, concern has been expressed in several countries about the immunogenicity of plasmaderived hepatitis B (HB) vaccine manufactured by a South Korean company (Cheil Jedang) and supplied at a 1·5 mg dose for neonates. The basis for this concern stems from studies by A Milne and colleagues1 in the Solomon Islands, in which results obtained from Cheil plasma-derived vaccine were compared with those from a DNA recombinant HB vaccine. Seroconversion to the Cheil vaccine was 58% versus 88% for the recombinant HB vaccine. These results were widely distributed by competing manufacturers of HB vaccines before their publication. Since this vaccine has been assessed by WHO and found acceptable in principle for purchase by United Nations agencies, we decided to collect data on this vaccine from several countries to see if there were difficulties with the immunogenicity under field conditions in developing countries. Our findings indicate that the poor seroconversion reported by Milne in the Solomon Islands was not found in several other studies, most conducted in developing countries. Various rates of sercoversion have been reported at meetings, the lowest being 83% (Philippines), but the range in others was from 93% (South Africa) to 100%
EUCLID study SIR—The June 21 commentary by Ping Wang1 on whether angiotensinconverting-enzyme (ACE) inhibitors should be given to normotensive patients who have insulin-dependent diabetes (IDDM), the EUCLID study group report (June 21, p 1787),2 and Gerjan Navis and colleagues’ June 28 commentary3 raise some interesting issues. The conclusion of the EUCLID group that “lisinopril shows that progressions of renal disease in normotensive IDDM patients with little or no albuminuria” is not convincing. Their conclusion is probably based on the significant reduction in the albumin excretion rate after lisinopril treatment in these patients who had microalbuminuria. However, delayed progression of renal disease means a change in the glomerular filtration rate (GFR), and that indice was not measured. By contrast, the GISEN group (June 25, p 1857)4 examined the effect of ramipril on decline in GFR and risk of terminal renal failure in protienuric non-diabetic nephropathy and found that “in multivariate analysis, as expected, a lower baseline GFR was significantly associated with an increased risk of reaching an endpoint in the longterm (p=0·0001)”. Thus, the message is clear that the use of ACE inhibitors benefits deterioration of GFR, independently of reduction of protienuria or not. A guideline should be decided for those patients who have massive protienuria, rapid decline in GFR, and are heading towards endstage renal disease with multiple complications. The comment by Navis
Vol 350 • October 11, 1997