- Email: [email protected]
Publicity and unpublished results
556
Overseas training for doctors from developing countries SIR,-Dr Patel and Dr Araya (Jan 11, p 110) state that "one for the dearth of research in developing countries is the lack of trained personnel", thereby again drawing attention to the belief created by doctors in the west and to the understandably frustrated expectations of overseas doctors returning back to their countries reason
with limited research facilities. But what kind of research and what type of training are they talking about? The Indian subcontinent has a doctor to population ratio ranging froml/1500 to 1/3000.1 What does it need more-adequate numbers of doctors delivering primary care, or expensive research in, for example, SPECT studies identifying brain infarcts associated with depression? What is regarded as routine research in rich countries is unnecessary in a poorly funded health-care system. Yet many people overlook the essential and appropriate research that is done-eg, oral rehydration therapy, leprosy vaccines-and that will continue to be done. Moreover, basic clinical research does not need a highly specialised and expensive research infrastructure. Clearly, every health system has to award priorities to its resource allocations-as in the Oregon approach.2 This approach emphasises that the American taxpayer is now considering whether better emergency services are more important than one liver transplant. If the trend is to allot resources mainly to basic clinical care, why should the taxpayers of third-world countries fund research that appeals to a handful of doctors who have received higher training in developed countries? What is higher training? Experience in specialties is certainly such for overseas doctors who leave their home countries with postgraduate degrees. Most overseas junior doctors in the UK come here after having already worked in their own countries for two years or more. Herein lies a fundamental difference: having had no working experience in his home country, Patel and Araya’s "Dr X" has expectations based solely on overseas training, and not on postgraduate training at home followed by higher training overseas. Patel and Araya also say that"... a senior registrar from the UK will find it nearly impossible to obtain a job at a similar level of seniority in an academic unit in some developing countries". Why should this be surprising? Senior registrars in psychiatry who have received all their training in the UK will be unable to cope in the Indian subcontinent mental health services, where, for instance, the mental health legislation is totally different. For the same reason we would have been naive to have expected to start as senior registrars or lecturers on our first appointments in the UK. Additionally, doctors on overseas sabbaticals have secure academic posts at home and, hence, higher chances of access to existing research facilities. Between us, we have a total of 11years of psychiatric experience in our countries and 4 years in the UK. Rather than disillusioned, we are, perhaps, in a position to make the best of our experience here on returning home. We not only agree with all their suggestions, but are also thankful to Patel and Araya for outlining the difficulties so succinctly. But, Sir, we do not consider ourselves to be in a "plight". Dr X is in no way representative of overseas doctors. Department of Psychiatry, St Mary’s Hospital, London W2 1NY, UK
NARESH GANDHI
Department of Psychiatry, St George’s Hospital, London SW17
PIYUSH JOHARI
Department of Psychiatry, St Mary’s Hospital
HAMID NALIYAWALA
1. World Health Organisation. World directory of medical schools. Geneva: WHO, 1988. 2. Dixon J, Welch HG. Priority setting: lessons from Oregon. Lancet 1991; 337: 891-94.
SIR,- The World Health Organisation, UK Overseas Development Administration, and other such international development agencies could profitably pay attention to the plea of Dr Patel and Dr Araya. Most overseas doctors would be intellectually and professionally far more satisfied if they could practise in their own countries. For reasons mainly related to economic uncertainty and these doctors’ inability to secure jobs for
which they are suitably qualified, they are trapped in the host country where they are rarely able to work in the specialty of their choice. This situation leads to a waste of scarce skilled manpower in developing countries and misuse of training resources of the host country. In the 1960s attention was focused on establishing links between teaching hospitals in the developed and developing world; in the 1970s primary health care became the preoccupation. Perhaps funding agencies should now direct their resources toward district hospitals, in which many returning doctors are well suited to work.’ Under the auspices of the aid organisations, serious consideration could be given to the notion of the twinning of two district hospitals-one in the developed world and the other in a developing country. Exchange visits of medical staff from various specialties would be invaluable and provide intellectual stimulation for doctors who are accustomed to work conditions in the developed world. Equipment rendered obsolete by technological advances in the developed world could be donated to the twinned hospital. This would be an invaluable asset if technological back-up and effective maintenance is provided-a frequent omission in aid programmes. The hospital league of friends will find it rewarding to take part in such schemes when they see the immense benefits that can accrue from a modest financial investment. Institution of such non-governmental voluntary projects are often characterised by great enthusiasm and flexibility in administration, planning, and employmentMost doctors returning to their home country would like to combine working in a well-run hospital with good facilities and private practice to provide financial security. In general their prospects are very good provided that they can survive the initial few years of financial struggle. Greater appreciation of these doctors’ troubles will hopefully soon lead to innovative steps by the aid organisations to find ways to alleviate the difficulties and to ensure that there is no further waste of this precious manpower. Funds allocated for training should include a component for resettlement, otherwise aid-funding agencies could be criticised on the grounds that training programmes represent a covert brain drain, not an aid programme. Many doctors still look to the west and the UK in particular for historical reasons; a continuing dialogue between British doctors and their overseas colleagues is one of the ways to give humanitarian help that should not be neglected. Public Health Laboratory, Musgrove Park Hospital,
Taunton TA1 5DB, UK
J. WYNNE JONES
1. Editorial. Front-line doctor. Lancet 1991; 338: 155-56. 2. Mavalankar DV. Health in India. Br Med J 1992; 302: 470.
Publicity and unpublished results SIR,-Professor Griffiths’ (Royal Free Hospital)
recent
appearance on national television informing the world at large that
by the use of acyclovir the death rate from HIV had been halved is at best premature, and at worst irresponsible. Patients locally, and I expect nationally, have been telephoning their doctors to ask when they are to receive acyclovir. The fact that his dramatic appearance has preceded any publication of the results put his colleagues in an embarrassing and difficult position. What is even more disturbing is to read in the Pharmaceutical Journal (Jan 4, 1992, p 10) a spokesman for Wellcome stating that the trial was not a true combination study of acyclovir with zidovudine and figures were unconfirmed. The clear impression given by Griffiths was that this was a combination study under controlled conditions and that the result was final. There is nothing to be gained and much harm to be done by such television appearances. Surely the responsible approach to such publicity is to report only the published results of material that has undergone peer review? Perhaps all doctors are of like mind, but, sadly, it may be time for a voluntary code of practice before further damage is done to the profession’s integrity. Department of Haematology, Central Laboratory, St Mary’s Hospital, Portsmouth PO3 6AG, UK
P.
J. GREEN
557
***’I’his letter has been shown to Professor Griffiths, whose reply follows.-ED. L. multicentre trial to which Dr Green refers was a double-blind comparison of acyclovir and placebo. The trial therapy was given in addition to antiretroviral drugs prescribed openly by each patient’s physician. Since most patients received these drugs, it is essential to consider the combined effect of both
SIR,- The
drug treatments.1 . Green also raises the important issue of when information from clinical trials should be made public. This has been done at several different stages for controlled trials of drugs in HIV-positive patients. Each of these approaches has advantages and disadvantages, and publicity has led to criticism from interested parties. The discussion of results only after formal publication has the advantage of ensuring peer review but introduces a delay of many months. In the rapidly changing AIDS treatment scene, this delay has led to accusations of excessive secrecy. A possible explanation for the acyclovir trial result is an effect of the drug on a viral cofactor that drives HIV replication. A cofactor effect can only be discerned if the data are examined to exclude the
possibility that the virus in question is acting opportunistically to cause disease in its own right.2 By analogy, the benefit of a treatment could only be attributed to inhibition of a cofactor effect if the drug did not reduce opportunistic disease caused by the same virus. This was the precise circumstance in which the acyclovir trial was stopped, and I briefed a medical correspondent about the notion of cofactor viruses. What I did not anticipate was that minor points in the briefing, such as the potential ultimate benefits of combination chemotherapy, would become major items of discussion, rather than the cofactor concept. The prominence given by journalists to an article depends on many factors other than its intrinsic merit. I was embarrassed by the publicity my briefing received and regret the anxiety that some people with HIV infection and their doctors may have had. It is inevitable that more trials in patients with HIV infection will be stopped, and an agreed protocol would be of benefit to all. Department of Virology, Royal Free Hospital School of Medicine, London NW3 2PF, UK
P. D. GRIFFITHS
1. Studies of ocular complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med 1992; 326: 213-20. 2. Webster A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS m haemophiliacs with human immunodeficiency virus infection. Lancet 1989; ii: 63-66.
Human
rights in Sudan
SIR,-The fundamentalist, military government of Sudan is notorious for its abuse of human rights. Its severe laws, discriminations, and punishments have been condemned by human rights organisations world wide. Among its victims are a large number of doctors, who have been detained without trial and tortured (often in secret houses). One doctor died in April, 1991, after torture in prison. Another was sentenced to death, but finally released in response to international protest. Most, but by no means all, are no longer in prison. Most have not been allowed to return to work and many have fled the country. One of those still in prison is Dr Ahmed Osman Siraj, president of the Sudanese Society of Psychiatrists, a senior lecturer in the University of Khartoum, and a member of our College. We have been attempting to gain his release, with a view to his coming to the UK for a period of personal and educational recuperation. So far, we have had no success. The regime has shown itself to be sensitive to world opinion. May we therefore call on Lancet readers world wide to write, on behalf of Dr Siraj, to the President of Sudan, Lieutenant-General al-Bashir, People’s Palace, PO Box 281, Khartoum, and to their local Sudanese embassies. Royal College of Psychiatrists, 17 Belgrave Square, London SW1X 8PG, UK
A. C. P. SIMS J. L. T. BIRLEY THOMAS BEWLEY
Acute pressure
area care
p 221) is a timely reminder that remain a serious problem. Nevertheless, there is still a scarcity of information on the incidence of these sores shortly after admission to hospital. Bliss’ figures for the frequency of sores in patients with fracture of the femoral neck seem alarmingly high ("over 60%"), and expecially so when a similar survey in Nottingham’ showed a rate of 42 3% in these patients. However, the definition of sores differed in these two surveys, and from one of the reports indirectly referred to by Bliss (Versluysen M, unpublished) the surveys can be equated by removing those patients who only have persistent discolouration of a pressure area (a potential sore) .2 When this is done Versluysen’s figures fall to 43%, which is very close to that recorded by Hawthorn and Nyquist’ who did not count potential sores.
SIR,-Dr Bliss’ report (Jan 25,
pressure
sores
Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
PETER T. LOWTHIAN
1. Hawthorn
PJ, Nyquist R. The incidence of pressure sores amongst a group of elderly patients with fractured neck of femur. Care Sci Pract 1988; 6: 3-7. 2. Lowthian PT. The classification and grading of pressure sores. Care Sci Pract 1987; 5: 5-9.
Molecular elimination of the minimal residual Ph1 clone with IFN&agr; in CML SIR,-Interferon-&agr; (IFNx) induces haematological remission in patients with chronic myelogenous leukaemia (CML).1-3 In a
most
patients, Ph1 chromosome disappearance has also been accompanied by the loss of an aberrant restriction fragment of the BCR gene after IFN therapy. 3-5 So far suppression of the Ph clone confirmed by the polymerase chain reaction (PCR) to detect bcrlabl hybrid transcripts has been reported in only one patient;6 the follow-up sample was, however, PCR positive. We report continuous suppression of bcrlabl hybrid transcripts and the time necessary to eliminate the minimal residual Ph1 from serial analysis. A 55-year-old man presented in September, 1987, with leucocytosis of 10-2 x 109/1. Bone-marrow examination revealed granulocytic hyperplasia and the typical translocation t(9;22)(q34;qll) in all metaphases (40/40 cells) carrying a bcr/abl rearrangement. We gave natural IFNot (’Sumiferon’, Sumitomo Pharmaceuticals, Japan) at a dose of 6x 106 U daily subcutaneously for CML. After 5 months of treatment the patient had achieved haematological remission and complete suppression of the Ph1 clone. Treatment was continued. In February, 1990, splenectomy was done and hydroxyurea (500 mg daily) was given in addition to IFNA thereafter. In all subsequent bone-marrow samples at months 5,14,19,28,41 and 43 and in spleen (at month 23), neither few
Ph1 chromosome nor bcrlabl rearrangement were detected. With a PCR procedure7 the result was positive in bone-marrow at month 19 and in spleen, but negative results were obtained at months 41 and 43. Although PCR-negative results may be attributable to downregulation of gene expression, our observation suggests that complete molecular elimination of the Ph’ clone takes more than 23 months, after reaching the limits of the sensitivity of Southern blot analysis. This might be important for the curative treatment of CML with IFNfx.
Departments of Haematology and Internal Medicine, Research Institute for Nuclear Medicine and Biology, Hiroshima University, Hiroshima 734, Japan
NOBUO OGUMA CHIHARU SHIGETA KATSUHIKO TAKAUCHI KIMIO TANAKA NANAO KAMADA HIRONORI KAWANO ATSUKI KURAMOTO
Talpaz M, Kantarijian HM, McCredie KB, Keating MJ, Trujillo J, Gutterman JU. Clinical investigations of human alpha interferon in chronic myelogenous leukemia. Blood 1987; 69: 1280-88. 2. Koyama S, Moriyama Y, Shibata A, et al. Clinical investigation of natural interferon alpha (HLBI) in chronic myelogenous leukemia: a multi-institutional cooperative study in Japan. Jpn J Cancer Chemother 1988; 15: 2959-66. 3. Talpaz M, Kantarijian H, Kurzrock R, Trujillo JM, Gutterman JU. Interferon-alpha produce sustained cytogenetic response in chronic myelogenous leukemia. Ann 1.
Intern Med 1991; 114: 532-38.
Overseas training for doctors from developing countries SIR,-Dr Patel and Dr Araya (Jan 11, p 110) state that "one for the dearth of research in developing countries is the lack of trained personnel", thereby again drawing attention to the belief created by doctors in the west and to the understandably frustrated expectations of overseas doctors returning back to their countries reason
with limited research facilities. But what kind of research and what type of training are they talking about? The Indian subcontinent has a doctor to population ratio ranging froml/1500 to 1/3000.1 What does it need more-adequate numbers of doctors delivering primary care, or expensive research in, for example, SPECT studies identifying brain infarcts associated with depression? What is regarded as routine research in rich countries is unnecessary in a poorly funded health-care system. Yet many people overlook the essential and appropriate research that is done-eg, oral rehydration therapy, leprosy vaccines-and that will continue to be done. Moreover, basic clinical research does not need a highly specialised and expensive research infrastructure. Clearly, every health system has to award priorities to its resource allocations-as in the Oregon approach.2 This approach emphasises that the American taxpayer is now considering whether better emergency services are more important than one liver transplant. If the trend is to allot resources mainly to basic clinical care, why should the taxpayers of third-world countries fund research that appeals to a handful of doctors who have received higher training in developed countries? What is higher training? Experience in specialties is certainly such for overseas doctors who leave their home countries with postgraduate degrees. Most overseas junior doctors in the UK come here after having already worked in their own countries for two years or more. Herein lies a fundamental difference: having had no working experience in his home country, Patel and Araya’s "Dr X" has expectations based solely on overseas training, and not on postgraduate training at home followed by higher training overseas. Patel and Araya also say that"... a senior registrar from the UK will find it nearly impossible to obtain a job at a similar level of seniority in an academic unit in some developing countries". Why should this be surprising? Senior registrars in psychiatry who have received all their training in the UK will be unable to cope in the Indian subcontinent mental health services, where, for instance, the mental health legislation is totally different. For the same reason we would have been naive to have expected to start as senior registrars or lecturers on our first appointments in the UK. Additionally, doctors on overseas sabbaticals have secure academic posts at home and, hence, higher chances of access to existing research facilities. Between us, we have a total of 11years of psychiatric experience in our countries and 4 years in the UK. Rather than disillusioned, we are, perhaps, in a position to make the best of our experience here on returning home. We not only agree with all their suggestions, but are also thankful to Patel and Araya for outlining the difficulties so succinctly. But, Sir, we do not consider ourselves to be in a "plight". Dr X is in no way representative of overseas doctors. Department of Psychiatry, St Mary’s Hospital, London W2 1NY, UK
NARESH GANDHI
Department of Psychiatry, St George’s Hospital, London SW17
PIYUSH JOHARI
Department of Psychiatry, St Mary’s Hospital
HAMID NALIYAWALA
1. World Health Organisation. World directory of medical schools. Geneva: WHO, 1988. 2. Dixon J, Welch HG. Priority setting: lessons from Oregon. Lancet 1991; 337: 891-94.
SIR,- The World Health Organisation, UK Overseas Development Administration, and other such international development agencies could profitably pay attention to the plea of Dr Patel and Dr Araya. Most overseas doctors would be intellectually and professionally far more satisfied if they could practise in their own countries. For reasons mainly related to economic uncertainty and these doctors’ inability to secure jobs for
which they are suitably qualified, they are trapped in the host country where they are rarely able to work in the specialty of their choice. This situation leads to a waste of scarce skilled manpower in developing countries and misuse of training resources of the host country. In the 1960s attention was focused on establishing links between teaching hospitals in the developed and developing world; in the 1970s primary health care became the preoccupation. Perhaps funding agencies should now direct their resources toward district hospitals, in which many returning doctors are well suited to work.’ Under the auspices of the aid organisations, serious consideration could be given to the notion of the twinning of two district hospitals-one in the developed world and the other in a developing country. Exchange visits of medical staff from various specialties would be invaluable and provide intellectual stimulation for doctors who are accustomed to work conditions in the developed world. Equipment rendered obsolete by technological advances in the developed world could be donated to the twinned hospital. This would be an invaluable asset if technological back-up and effective maintenance is provided-a frequent omission in aid programmes. The hospital league of friends will find it rewarding to take part in such schemes when they see the immense benefits that can accrue from a modest financial investment. Institution of such non-governmental voluntary projects are often characterised by great enthusiasm and flexibility in administration, planning, and employmentMost doctors returning to their home country would like to combine working in a well-run hospital with good facilities and private practice to provide financial security. In general their prospects are very good provided that they can survive the initial few years of financial struggle. Greater appreciation of these doctors’ troubles will hopefully soon lead to innovative steps by the aid organisations to find ways to alleviate the difficulties and to ensure that there is no further waste of this precious manpower. Funds allocated for training should include a component for resettlement, otherwise aid-funding agencies could be criticised on the grounds that training programmes represent a covert brain drain, not an aid programme. Many doctors still look to the west and the UK in particular for historical reasons; a continuing dialogue between British doctors and their overseas colleagues is one of the ways to give humanitarian help that should not be neglected. Public Health Laboratory, Musgrove Park Hospital,
Taunton TA1 5DB, UK
J. WYNNE JONES
1. Editorial. Front-line doctor. Lancet 1991; 338: 155-56. 2. Mavalankar DV. Health in India. Br Med J 1992; 302: 470.
Publicity and unpublished results SIR,-Professor Griffiths’ (Royal Free Hospital)
recent
appearance on national television informing the world at large that
by the use of acyclovir the death rate from HIV had been halved is at best premature, and at worst irresponsible. Patients locally, and I expect nationally, have been telephoning their doctors to ask when they are to receive acyclovir. The fact that his dramatic appearance has preceded any publication of the results put his colleagues in an embarrassing and difficult position. What is even more disturbing is to read in the Pharmaceutical Journal (Jan 4, 1992, p 10) a spokesman for Wellcome stating that the trial was not a true combination study of acyclovir with zidovudine and figures were unconfirmed. The clear impression given by Griffiths was that this was a combination study under controlled conditions and that the result was final. There is nothing to be gained and much harm to be done by such television appearances. Surely the responsible approach to such publicity is to report only the published results of material that has undergone peer review? Perhaps all doctors are of like mind, but, sadly, it may be time for a voluntary code of practice before further damage is done to the profession’s integrity. Department of Haematology, Central Laboratory, St Mary’s Hospital, Portsmouth PO3 6AG, UK
P.
J. GREEN
557
***’I’his letter has been shown to Professor Griffiths, whose reply follows.-ED. L. multicentre trial to which Dr Green refers was a double-blind comparison of acyclovir and placebo. The trial therapy was given in addition to antiretroviral drugs prescribed openly by each patient’s physician. Since most patients received these drugs, it is essential to consider the combined effect of both
SIR,- The
drug treatments.1 . Green also raises the important issue of when information from clinical trials should be made public. This has been done at several different stages for controlled trials of drugs in HIV-positive patients. Each of these approaches has advantages and disadvantages, and publicity has led to criticism from interested parties. The discussion of results only after formal publication has the advantage of ensuring peer review but introduces a delay of many months. In the rapidly changing AIDS treatment scene, this delay has led to accusations of excessive secrecy. A possible explanation for the acyclovir trial result is an effect of the drug on a viral cofactor that drives HIV replication. A cofactor effect can only be discerned if the data are examined to exclude the
possibility that the virus in question is acting opportunistically to cause disease in its own right.2 By analogy, the benefit of a treatment could only be attributed to inhibition of a cofactor effect if the drug did not reduce opportunistic disease caused by the same virus. This was the precise circumstance in which the acyclovir trial was stopped, and I briefed a medical correspondent about the notion of cofactor viruses. What I did not anticipate was that minor points in the briefing, such as the potential ultimate benefits of combination chemotherapy, would become major items of discussion, rather than the cofactor concept. The prominence given by journalists to an article depends on many factors other than its intrinsic merit. I was embarrassed by the publicity my briefing received and regret the anxiety that some people with HIV infection and their doctors may have had. It is inevitable that more trials in patients with HIV infection will be stopped, and an agreed protocol would be of benefit to all. Department of Virology, Royal Free Hospital School of Medicine, London NW3 2PF, UK
P. D. GRIFFITHS
1. Studies of ocular complications of AIDS Research Group, in collaboration with the AIDS Clinical Trials Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N Engl J Med 1992; 326: 213-20. 2. Webster A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS m haemophiliacs with human immunodeficiency virus infection. Lancet 1989; ii: 63-66.
Human
rights in Sudan
SIR,-The fundamentalist, military government of Sudan is notorious for its abuse of human rights. Its severe laws, discriminations, and punishments have been condemned by human rights organisations world wide. Among its victims are a large number of doctors, who have been detained without trial and tortured (often in secret houses). One doctor died in April, 1991, after torture in prison. Another was sentenced to death, but finally released in response to international protest. Most, but by no means all, are no longer in prison. Most have not been allowed to return to work and many have fled the country. One of those still in prison is Dr Ahmed Osman Siraj, president of the Sudanese Society of Psychiatrists, a senior lecturer in the University of Khartoum, and a member of our College. We have been attempting to gain his release, with a view to his coming to the UK for a period of personal and educational recuperation. So far, we have had no success. The regime has shown itself to be sensitive to world opinion. May we therefore call on Lancet readers world wide to write, on behalf of Dr Siraj, to the President of Sudan, Lieutenant-General al-Bashir, People’s Palace, PO Box 281, Khartoum, and to their local Sudanese embassies. Royal College of Psychiatrists, 17 Belgrave Square, London SW1X 8PG, UK
A. C. P. SIMS J. L. T. BIRLEY THOMAS BEWLEY
Acute pressure
area care
p 221) is a timely reminder that remain a serious problem. Nevertheless, there is still a scarcity of information on the incidence of these sores shortly after admission to hospital. Bliss’ figures for the frequency of sores in patients with fracture of the femoral neck seem alarmingly high ("over 60%"), and expecially so when a similar survey in Nottingham’ showed a rate of 42 3% in these patients. However, the definition of sores differed in these two surveys, and from one of the reports indirectly referred to by Bliss (Versluysen M, unpublished) the surveys can be equated by removing those patients who only have persistent discolouration of a pressure area (a potential sore) .2 When this is done Versluysen’s figures fall to 43%, which is very close to that recorded by Hawthorn and Nyquist’ who did not count potential sores.
SIR,-Dr Bliss’ report (Jan 25,
pressure
sores
Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
PETER T. LOWTHIAN
1. Hawthorn
PJ, Nyquist R. The incidence of pressure sores amongst a group of elderly patients with fractured neck of femur. Care Sci Pract 1988; 6: 3-7. 2. Lowthian PT. The classification and grading of pressure sores. Care Sci Pract 1987; 5: 5-9.
Molecular elimination of the minimal residual Ph1 clone with IFN&agr; in CML SIR,-Interferon-&agr; (IFNx) induces haematological remission in patients with chronic myelogenous leukaemia (CML).1-3 In a
most
patients, Ph1 chromosome disappearance has also been accompanied by the loss of an aberrant restriction fragment of the BCR gene after IFN therapy. 3-5 So far suppression of the Ph clone confirmed by the polymerase chain reaction (PCR) to detect bcrlabl hybrid transcripts has been reported in only one patient;6 the follow-up sample was, however, PCR positive. We report continuous suppression of bcrlabl hybrid transcripts and the time necessary to eliminate the minimal residual Ph1 from serial analysis. A 55-year-old man presented in September, 1987, with leucocytosis of 10-2 x 109/1. Bone-marrow examination revealed granulocytic hyperplasia and the typical translocation t(9;22)(q34;qll) in all metaphases (40/40 cells) carrying a bcr/abl rearrangement. We gave natural IFNot (’Sumiferon’, Sumitomo Pharmaceuticals, Japan) at a dose of 6x 106 U daily subcutaneously for CML. After 5 months of treatment the patient had achieved haematological remission and complete suppression of the Ph1 clone. Treatment was continued. In February, 1990, splenectomy was done and hydroxyurea (500 mg daily) was given in addition to IFNA thereafter. In all subsequent bone-marrow samples at months 5,14,19,28,41 and 43 and in spleen (at month 23), neither few
Ph1 chromosome nor bcrlabl rearrangement were detected. With a PCR procedure7 the result was positive in bone-marrow at month 19 and in spleen, but negative results were obtained at months 41 and 43. Although PCR-negative results may be attributable to downregulation of gene expression, our observation suggests that complete molecular elimination of the Ph’ clone takes more than 23 months, after reaching the limits of the sensitivity of Southern blot analysis. This might be important for the curative treatment of CML with IFNfx.
Departments of Haematology and Internal Medicine, Research Institute for Nuclear Medicine and Biology, Hiroshima University, Hiroshima 734, Japan
NOBUO OGUMA CHIHARU SHIGETA KATSUHIKO TAKAUCHI KIMIO TANAKA NANAO KAMADA HIRONORI KAWANO ATSUKI KURAMOTO
Talpaz M, Kantarijian HM, McCredie KB, Keating MJ, Trujillo J, Gutterman JU. Clinical investigations of human alpha interferon in chronic myelogenous leukemia. Blood 1987; 69: 1280-88. 2. Koyama S, Moriyama Y, Shibata A, et al. Clinical investigation of natural interferon alpha (HLBI) in chronic myelogenous leukemia: a multi-institutional cooperative study in Japan. Jpn J Cancer Chemother 1988; 15: 2959-66. 3. Talpaz M, Kantarijian H, Kurzrock R, Trujillo JM, Gutterman JU. Interferon-alpha produce sustained cytogenetic response in chronic myelogenous leukemia. Ann 1.
Intern Med 1991; 114: 532-38.