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Infection and cancer
CORRESPONDENCE
Patients’ dying wishes Sir—A relative had bequeathed her body for medical research but was rejected because, 9 days before her death at age 84 years, she had been operated on and the wound was unhealed when she died. The family had, at the start of her sojourn in hospital 3 months earlier, requested palliative care only, since she was clearly in the last stages of what had been an active and independent life. However, the gerontology team persuaded them to accept intervention feeding and antibiotics, and the patient contracted meticillin-resistant Staphylococcus aureus and Clostridium difficile. The family were handicapped in taking a firm stance by the lack of clear instructions from their relative about the final stages of life. The cost to the National Health Service for the patient’s 3-month stay in hospital is reckoned as being about UK£29 000, plus the cost of a hipjoint operation after a fall. This amount does not take into consideration the distress endured by the patient and family. The series of Reith Lectures1 has encouraged a responsible and clearsighted attitude to end of life issues. Is it not time for a form to be made available, and promoted at all family physicians’ surgeries, to provide unequivocable instructions for doctors and families about unwelcome medical intervention at the end of life? Sally Miles 37 Farquhar Street, Hertford SG14 3BW, UK (e-mail: [email protected]) 1
The end of age. www.bbc.co.uk/radio4/reith2001/inforeith. shtml (accessed June 7, 2001).
Infection and cancer Sir—The report by L J Kinlen and A Balkwill (March 17, p 858)1 raises a provocative question about the possible relation of infection to childhood leukaemia. However, their emphasis on an underlying infectious cause seems misplaced, since it implies a specific aetiological agent. It is just as reasonable to put forward the hypothesis that it is the host response, rather than the specific nature of the infection, that plays an important part. The host processing of an infection includes leucocyte recruitment and cell multiplication. Each cell division presents a new opportunity for gene mutation if an error occurs during DNA replication that eludes DNA repair mechanisms.
THE LANCET • Vol 358 • July 14, 2001
If the mutation happens to land on a coding portion of a gene that controls regulation of cell proliferation or DNA repair, oncogenesis is a possible result. Kinlen and Balkwill describe circumstances during World War II wherein host defences of a formerly somewhat isolated indigenous child population are confronted with an intense infection dose over a short period of time, increasing the probability of a DNA mistake during frequent, successive cycles of leucocyte recruitment. These considerations invite the speculation of a possible increase in leukaemia incidence among health-care workers exposed to a high rate of infection compared with specialists who encounter infections less frequently. Moreover, one wonders whether young children in daycare have a higher incidence of leukaemia compared with those who remain at home.
between ages 2 and 5 years is due to the effects of many infections that previously occurred in infancy, but which are now delayed to these ages because of modern improvements in hygiene. But this change will not explain the substantial excess of leukaemia in children younger than 2 years in pooled studies of unusual population mixing. The suggestion that the children of parents in high contact occupations might be at greater risk of leukaemia has already been investigated.4 Positive evidence found (only in rural areas where the prevalence of susceptible individuals is higher than average) again points to an infective basis.
Ronald J Kallen
2
Children’s Medical Group, 6213 10th Avenue, Kenosha, WI 53143, USA 1
Kinlen LJ, Balkwill A. Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK. Lancet 2001; 357: 858.
Authors’ reply Sir—We presented epidemiological evidence of infectivity underlying childhood leukaemia, which supported similar findings in a series of other situations of rural population Most infection-based mixing.1,2 diseases have turned out to be due to specific agents and we see no reason at this stage to prefer a more novel explanation for this disese. Epidemiological evidence of infectivity has been the spur in the past to the successful search for specific agents, including those underlying such malignant diseases as cervical cancer and Kaposi’s sarcoma. We hope, therefore, that microbiologists will pursue this question in relation to childhood leukaemia by the new methods that have become available. Ronald Kallen’s suggestion that childhood leukaemia may be caused by non-specific infections probably requires some modification to accommodate the fact that the incidence of the disease in many countries has increased during a period in which childhood infections have declined. particularly Greaves’ hypothesis3 addresses this point by postulating that the emergence of the peak in incidence of acute lymphoblastic leukaemia in developed countries
*L J Kinlen, A Balkwill Cancer Research Campaign Epidemiology Unit, Department of Public Health, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
3
4
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 2001; 71: 1–5. Dol IR. The Seascale cluster: a probable explanation. Br J Cancer 1999; 81: 3–5. Greaves M. A natural history for pediatric acute lymphoblastic leukemia. Blood 1993; 82: 1043–51. Kinlen LJ, Bramald S. Paternal occupational contact level and childhood leukaemia in rural Scotland: a casecontrol study. Br J Cancer 2001; 84: 1002–07.
Sir—Fran Balkwill and Alberto Mantovani (Feb 17, p 539),1 I think, should have included the name of William B Coley (1862–1936) in their review of Rudolf Virchow’s work. I will by no means depreciate Virchow, but stress the clinical relevance of Coley`s work for the inflammation-cancer connection. Coley translated the observation of tumour regression concomitant with infection into a treatment—the Coley toxins (Coley’s mixed toxins or Coley’s vaccine) consisting of heatkilled or sterile filtrated cultures of Streptococcus pyogenes and Serratia marcescens. Thus, the toxins contained some of the most potent immuneregulatory substances, such as lipopolysaccharides, exotoxins (also as superantigens), enzymes such as streptokinase, as well as an unimaginable amount of other bacterial antigens. That the Coley toxins could cure patients with extensive inoperable tumours is documented, but the results were unpredictable, which is not surprising considering where bacteriology and immunology stood at that time.2 Tumour necrosis factor (TNF) was
155
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Patients’ dying wishes Sir—A relative had bequeathed her body for medical research but was rejected because, 9 days before her death at age 84 years, she had been operated on and the wound was unhealed when she died. The family had, at the start of her sojourn in hospital 3 months earlier, requested palliative care only, since she was clearly in the last stages of what had been an active and independent life. However, the gerontology team persuaded them to accept intervention feeding and antibiotics, and the patient contracted meticillin-resistant Staphylococcus aureus and Clostridium difficile. The family were handicapped in taking a firm stance by the lack of clear instructions from their relative about the final stages of life. The cost to the National Health Service for the patient’s 3-month stay in hospital is reckoned as being about UK£29 000, plus the cost of a hipjoint operation after a fall. This amount does not take into consideration the distress endured by the patient and family. The series of Reith Lectures1 has encouraged a responsible and clearsighted attitude to end of life issues. Is it not time for a form to be made available, and promoted at all family physicians’ surgeries, to provide unequivocable instructions for doctors and families about unwelcome medical intervention at the end of life? Sally Miles 37 Farquhar Street, Hertford SG14 3BW, UK (e-mail: [email protected]) 1
The end of age. www.bbc.co.uk/radio4/reith2001/inforeith. shtml (accessed June 7, 2001).
Infection and cancer Sir—The report by L J Kinlen and A Balkwill (March 17, p 858)1 raises a provocative question about the possible relation of infection to childhood leukaemia. However, their emphasis on an underlying infectious cause seems misplaced, since it implies a specific aetiological agent. It is just as reasonable to put forward the hypothesis that it is the host response, rather than the specific nature of the infection, that plays an important part. The host processing of an infection includes leucocyte recruitment and cell multiplication. Each cell division presents a new opportunity for gene mutation if an error occurs during DNA replication that eludes DNA repair mechanisms.
THE LANCET • Vol 358 • July 14, 2001
If the mutation happens to land on a coding portion of a gene that controls regulation of cell proliferation or DNA repair, oncogenesis is a possible result. Kinlen and Balkwill describe circumstances during World War II wherein host defences of a formerly somewhat isolated indigenous child population are confronted with an intense infection dose over a short period of time, increasing the probability of a DNA mistake during frequent, successive cycles of leucocyte recruitment. These considerations invite the speculation of a possible increase in leukaemia incidence among health-care workers exposed to a high rate of infection compared with specialists who encounter infections less frequently. Moreover, one wonders whether young children in daycare have a higher incidence of leukaemia compared with those who remain at home.
between ages 2 and 5 years is due to the effects of many infections that previously occurred in infancy, but which are now delayed to these ages because of modern improvements in hygiene. But this change will not explain the substantial excess of leukaemia in children younger than 2 years in pooled studies of unusual population mixing. The suggestion that the children of parents in high contact occupations might be at greater risk of leukaemia has already been investigated.4 Positive evidence found (only in rural areas where the prevalence of susceptible individuals is higher than average) again points to an infective basis.
Ronald J Kallen
2
Children’s Medical Group, 6213 10th Avenue, Kenosha, WI 53143, USA 1
Kinlen LJ, Balkwill A. Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK. Lancet 2001; 357: 858.
Authors’ reply Sir—We presented epidemiological evidence of infectivity underlying childhood leukaemia, which supported similar findings in a series of other situations of rural population Most infection-based mixing.1,2 diseases have turned out to be due to specific agents and we see no reason at this stage to prefer a more novel explanation for this disese. Epidemiological evidence of infectivity has been the spur in the past to the successful search for specific agents, including those underlying such malignant diseases as cervical cancer and Kaposi’s sarcoma. We hope, therefore, that microbiologists will pursue this question in relation to childhood leukaemia by the new methods that have become available. Ronald Kallen’s suggestion that childhood leukaemia may be caused by non-specific infections probably requires some modification to accommodate the fact that the incidence of the disease in many countries has increased during a period in which childhood infections have declined. particularly Greaves’ hypothesis3 addresses this point by postulating that the emergence of the peak in incidence of acute lymphoblastic leukaemia in developed countries
*L J Kinlen, A Balkwill Cancer Research Campaign Epidemiology Unit, Department of Public Health, University of Oxford, Radcliffe Infirmary, Oxford OX2 6HE, UK 1
3
4
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer 2001; 71: 1–5. Dol IR. The Seascale cluster: a probable explanation. Br J Cancer 1999; 81: 3–5. Greaves M. A natural history for pediatric acute lymphoblastic leukemia. Blood 1993; 82: 1043–51. Kinlen LJ, Bramald S. Paternal occupational contact level and childhood leukaemia in rural Scotland: a casecontrol study. Br J Cancer 2001; 84: 1002–07.
Sir—Fran Balkwill and Alberto Mantovani (Feb 17, p 539),1 I think, should have included the name of William B Coley (1862–1936) in their review of Rudolf Virchow’s work. I will by no means depreciate Virchow, but stress the clinical relevance of Coley`s work for the inflammation-cancer connection. Coley translated the observation of tumour regression concomitant with infection into a treatment—the Coley toxins (Coley’s mixed toxins or Coley’s vaccine) consisting of heatkilled or sterile filtrated cultures of Streptococcus pyogenes and Serratia marcescens. Thus, the toxins contained some of the most potent immuneregulatory substances, such as lipopolysaccharides, exotoxins (also as superantigens), enzymes such as streptokinase, as well as an unimaginable amount of other bacterial antigens. That the Coley toxins could cure patients with extensive inoperable tumours is documented, but the results were unpredictable, which is not surprising considering where bacteriology and immunology stood at that time.2 Tumour necrosis factor (TNF) was
155
For personal use. Only reproduce with permission from The Lancet Publishing Group.