1553
not
undergoing reoperation;
a
difference in
outcome cannot
be
assumed.
Treatment of
cancer
by infectious nucleic
acid
Donor scarcity requires difficult clinical and ethical decisions, but also compels us to make the best use of a limited resource. We believe that there is already convincing evidence that acute cardiac retransplantation is not justified while there is a critical shortage of donor organs.
Transplant Unit, Papworth Hospital, Cambridge CB3 8RE, UK
PAUL MULLINS JOHN SCOTT ANOOP CHAUHAN TIM GRAHAM DAN ARAVOT STEVE LARGE PETER SCHOFIELD JOHN WALLWORK
1. Chaffin
JS. Donor organ availability and transplant coordination. In: Cooper DKC, Novitzky D, eds. The transplantation and replacement of thoracic organs. New York: Kluwer, 1991: 33-40. 2. Mullins PA, Scott JP, Dunning JP, et al. Cardiac transplant waiting lists, donor shortage and retransplantation: implications for using donor hearts. Am J Cardiol (in press). 3. Kriett JM, Kaye MP. The Registry of the International Society of Heart Transplantation: seventh official report-1990. J Heart Transplant 1990; 9: 323-30.
Liver transplantation for severe von Willebrand’s disease SIR,-Professor Mannucci and colleagues (May 4, p 1105) a patient with von Willebrand’s disease who received a liver transplant. Post-transplant there was an increase in factor VIII (by 10-20%) and von Willebrand factor antigen (vWFAg) from 0-04% to 0’92-1’02%, without an improvement in bleeding time or ristocetin cofactor. They suggested that the increased vWFAg describe
was due to production of vWF from the donor liver’s endothelium. They also concluded that liver endothelium produces only a small proportion of the plasma pool of vWF. These conclusions are based on two assumptions that may not be valid. First, that donor endothelium remains intact after transplantation, and second, that there are no other causes of an increase in vWFAg and factor VIII after transplantation. However, re-endothelialisation of donor heart1 and kidney2 with recipient endothelial cells can occur as early as three months after grafting. Increased plasma concentrations of vWFAg and factor VIII are found in "steady state" heart transplant recipients.3,4 Similarly, renal transplant recipients have increased factor VIIICs and vWFAg activities, especially when associated with cyclosporin nephrotoxicity.1 These changes have been attributed to cyclosporin. Mannucci et al do not state what immunosuppression their patient received but we assume that the regimen included
activity
cyclosporin. The experience
from this patient indicates that liver transplantation is not an appropriate treatment for von Willebrand’s
disease. However, the contribution of liver endothelium to the plasma pool of vWF cannot be assessed from this patient until survival of functional donor liver endothelium is established. The increase in plasma vWF after transplantation is probably of recipient origin (as suggested by the increase in vWFAg without functional improvement), possibly due to an effect of
cyclosporin. Department of Research Haematology, Harefield Hospital, Middlesex UB9 6JH, UK
SIR,—Your April 6 editorial on topical BCG for recurrent superficial bladder cancer illustrates the use of microbiological agents for treating malignant disease. BCG acts indirectly by stimulating an enhanced immunological response; however, a different approach could be the direct destruction of tumour cells by other microbiological methods. Malignant cells are unduly susceptible to a wide variety of viruses,1 as are cells transformed during tissue culture (the in-vitro equivalent of malignancy). Thus hela cells, derived from a cervical carcinoma, support the growth not only of many human viruses, including ones incapable of causing infection of the cervix clinically, but also some viruses normally restricted to non-human animal hosts. It had therefore been hoped that the cytopathic effect (CPE), whereby the infected cell is destroyed with the release of new virus particles, might be exploited clinically by treating cancer patients with relatively non-pathogenic viruses. So far such attempts have been unsuccessful, though instances are recorded of temporary remissions in patients with terminal leukaemia and other malignancies.2.2 A major factor limiting this attack is the rapid development of immunity to the virus, thereby inactivating the agent and bringing any tumour-cell destruction to a halt.3Might this difficulty be overcome by administering not live virus, but infectious viral nucleic acid instead? The nucleic acid genomes, DNA or RNA, of some viruses are in themselves infectious if given alone, both in vitro or in vivo. This is usually determined by whether viral replication needs viral enzymes in addition to the nucleic acid (non-infectious nucleic acids), or if the cell’s own enzymes can be utilised instead (infectious nucleic acids) 4 The advantage of using infectious nucleic acid is that although cells infected and then killed would release whole virus particles into the body with a consequent antibody response, this immunity would be directed specifically against the proteins of the virus and not its nucleic acid (the body does not normally react immunologically to nucleic acidss). Hence repeated doses of nucleic acid could be administered without being inactivated by immune mechanisms, thereby producing yet more CPE destruction of tumour cells. In theory, enzymatic breakdown of nucleic acids by bodily nucleases could be a limitation, but this is less likely to be a problem with DNA than with RNA. It would be axiomatic that the virus was one to which the malignant cells were sensitive, but which did not cause significant damage to the healthy tissues. Possibly, then, a combination of infectious viral nucleic acids, given either concomitantly or in sequence, might prove useful in treating patients with advanced cancers. PHLS Centre for Applied Microbiology and Research, Porton Down SP4 0JG, UK
P. M. SUTTON
1. Bumet FM. Immunological surveillance. Sydney: Pergamon, 1970: 140. 2. Gutterman JU, Hersh EM. Immunotherapy. In: Holland JF, Frei E, eds. Cancer medicine. Philadelphia: Lea and Febiger, 1982: 1108. 3. Webb HE, Gordon Smith CE. Viruses in the treatment of cancer. Lancet 1970; i: 1206-09. 4. White DO, Fenner FJ. Medical virology. Orlando, Florida: Academic Press, 1986: 11. 5. Goust JM. Systemic lupus erythematosus In. Virella G, Goust JM, Fudenberg HH, eds. Introduction to medical immunology. New York. Marcel Dekker, 1990: 452.
BEVERLEY J. HUNT
1 O’Connell JO, Renlund DG, Bristow MR, Hammond EH. Detection of allograft endothelial cells of recipient origin following ABO-compatible nonidentical cardiac transplantation. Transplantation 1991; 51: 438-42. 2. Sedmak DD, Sharma HM, Czaijka CM, Ferguson RM. Recipient endothelialization of renal allografts. Transplantation 1988; 46: 907 3. Hunt BJ, Segal H, Yacoub M. Endothelial cell haemostatic function after heart transplantation. Transplant Proc 1991; 23: 1182-83. 4. Hunt BJ, Segal H, Yacoub M. Haemostatic changes after heart transplantation and their relationship to accelerated coronary sclerosis. Transplant Proc 1991; 23: 1233-35. 5. Vanrenterghem Y, Roels L, Lerut T, et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients Lancet 1985; i: 999-1002. 6. Brown Z, Neild GH, Willoughby JJ, Somia NV, Cameron SJ. Increased factor VIII as an index of vascular injury in cyclosporin nephrotoxicity. Transplantation 1986; 42: 150-53
Cytotoxic cross-matching for organ transplantation SIR,-Renal graft survival is improved by optimum or "beneficial" HLA-matching and transplant units are encouraged to exchange kidneys that can safely tolerate up to 48 h of storage at 0-4°C.1 However, the fmal arbiter of organ allocation is not HLA-match but rather cytotoxic cross-match between recipient serum and lymphocytes isolated from donor spleen or lymph node, which are transported with the organ at room temperature.2,3 We recently received a kidney that was said to be a "beneficial match" after positive cross-matching at another centre. Although the organ was potentially viable, the cross-match was impossible because all available lymphocytes were dead. We undertook a survey to assess
not
undergoing reoperation;
a
difference in
outcome cannot
be
assumed.
Treatment of
cancer
by infectious nucleic
acid
Donor scarcity requires difficult clinical and ethical decisions, but also compels us to make the best use of a limited resource. We believe that there is already convincing evidence that acute cardiac retransplantation is not justified while there is a critical shortage of donor organs.
Transplant Unit, Papworth Hospital, Cambridge CB3 8RE, UK
PAUL MULLINS JOHN SCOTT ANOOP CHAUHAN TIM GRAHAM DAN ARAVOT STEVE LARGE PETER SCHOFIELD JOHN WALLWORK
1. Chaffin
JS. Donor organ availability and transplant coordination. In: Cooper DKC, Novitzky D, eds. The transplantation and replacement of thoracic organs. New York: Kluwer, 1991: 33-40. 2. Mullins PA, Scott JP, Dunning JP, et al. Cardiac transplant waiting lists, donor shortage and retransplantation: implications for using donor hearts. Am J Cardiol (in press). 3. Kriett JM, Kaye MP. The Registry of the International Society of Heart Transplantation: seventh official report-1990. J Heart Transplant 1990; 9: 323-30.
Liver transplantation for severe von Willebrand’s disease SIR,-Professor Mannucci and colleagues (May 4, p 1105) a patient with von Willebrand’s disease who received a liver transplant. Post-transplant there was an increase in factor VIII (by 10-20%) and von Willebrand factor antigen (vWFAg) from 0-04% to 0’92-1’02%, without an improvement in bleeding time or ristocetin cofactor. They suggested that the increased vWFAg describe
was due to production of vWF from the donor liver’s endothelium. They also concluded that liver endothelium produces only a small proportion of the plasma pool of vWF. These conclusions are based on two assumptions that may not be valid. First, that donor endothelium remains intact after transplantation, and second, that there are no other causes of an increase in vWFAg and factor VIII after transplantation. However, re-endothelialisation of donor heart1 and kidney2 with recipient endothelial cells can occur as early as three months after grafting. Increased plasma concentrations of vWFAg and factor VIII are found in "steady state" heart transplant recipients.3,4 Similarly, renal transplant recipients have increased factor VIIICs and vWFAg activities, especially when associated with cyclosporin nephrotoxicity.1 These changes have been attributed to cyclosporin. Mannucci et al do not state what immunosuppression their patient received but we assume that the regimen included
activity
cyclosporin. The experience
from this patient indicates that liver transplantation is not an appropriate treatment for von Willebrand’s
disease. However, the contribution of liver endothelium to the plasma pool of vWF cannot be assessed from this patient until survival of functional donor liver endothelium is established. The increase in plasma vWF after transplantation is probably of recipient origin (as suggested by the increase in vWFAg without functional improvement), possibly due to an effect of
cyclosporin. Department of Research Haematology, Harefield Hospital, Middlesex UB9 6JH, UK
SIR,—Your April 6 editorial on topical BCG for recurrent superficial bladder cancer illustrates the use of microbiological agents for treating malignant disease. BCG acts indirectly by stimulating an enhanced immunological response; however, a different approach could be the direct destruction of tumour cells by other microbiological methods. Malignant cells are unduly susceptible to a wide variety of viruses,1 as are cells transformed during tissue culture (the in-vitro equivalent of malignancy). Thus hela cells, derived from a cervical carcinoma, support the growth not only of many human viruses, including ones incapable of causing infection of the cervix clinically, but also some viruses normally restricted to non-human animal hosts. It had therefore been hoped that the cytopathic effect (CPE), whereby the infected cell is destroyed with the release of new virus particles, might be exploited clinically by treating cancer patients with relatively non-pathogenic viruses. So far such attempts have been unsuccessful, though instances are recorded of temporary remissions in patients with terminal leukaemia and other malignancies.2.2 A major factor limiting this attack is the rapid development of immunity to the virus, thereby inactivating the agent and bringing any tumour-cell destruction to a halt.3Might this difficulty be overcome by administering not live virus, but infectious viral nucleic acid instead? The nucleic acid genomes, DNA or RNA, of some viruses are in themselves infectious if given alone, both in vitro or in vivo. This is usually determined by whether viral replication needs viral enzymes in addition to the nucleic acid (non-infectious nucleic acids), or if the cell’s own enzymes can be utilised instead (infectious nucleic acids) 4 The advantage of using infectious nucleic acid is that although cells infected and then killed would release whole virus particles into the body with a consequent antibody response, this immunity would be directed specifically against the proteins of the virus and not its nucleic acid (the body does not normally react immunologically to nucleic acidss). Hence repeated doses of nucleic acid could be administered without being inactivated by immune mechanisms, thereby producing yet more CPE destruction of tumour cells. In theory, enzymatic breakdown of nucleic acids by bodily nucleases could be a limitation, but this is less likely to be a problem with DNA than with RNA. It would be axiomatic that the virus was one to which the malignant cells were sensitive, but which did not cause significant damage to the healthy tissues. Possibly, then, a combination of infectious viral nucleic acids, given either concomitantly or in sequence, might prove useful in treating patients with advanced cancers. PHLS Centre for Applied Microbiology and Research, Porton Down SP4 0JG, UK
P. M. SUTTON
1. Bumet FM. Immunological surveillance. Sydney: Pergamon, 1970: 140. 2. Gutterman JU, Hersh EM. Immunotherapy. In: Holland JF, Frei E, eds. Cancer medicine. Philadelphia: Lea and Febiger, 1982: 1108. 3. Webb HE, Gordon Smith CE. Viruses in the treatment of cancer. Lancet 1970; i: 1206-09. 4. White DO, Fenner FJ. Medical virology. Orlando, Florida: Academic Press, 1986: 11. 5. Goust JM. Systemic lupus erythematosus In. Virella G, Goust JM, Fudenberg HH, eds. Introduction to medical immunology. New York. Marcel Dekker, 1990: 452.
BEVERLEY J. HUNT
1 O’Connell JO, Renlund DG, Bristow MR, Hammond EH. Detection of allograft endothelial cells of recipient origin following ABO-compatible nonidentical cardiac transplantation. Transplantation 1991; 51: 438-42. 2. Sedmak DD, Sharma HM, Czaijka CM, Ferguson RM. Recipient endothelialization of renal allografts. Transplantation 1988; 46: 907 3. Hunt BJ, Segal H, Yacoub M. Endothelial cell haemostatic function after heart transplantation. Transplant Proc 1991; 23: 1182-83. 4. Hunt BJ, Segal H, Yacoub M. Haemostatic changes after heart transplantation and their relationship to accelerated coronary sclerosis. Transplant Proc 1991; 23: 1233-35. 5. Vanrenterghem Y, Roels L, Lerut T, et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients Lancet 1985; i: 999-1002. 6. Brown Z, Neild GH, Willoughby JJ, Somia NV, Cameron SJ. Increased factor VIII as an index of vascular injury in cyclosporin nephrotoxicity. Transplantation 1986; 42: 150-53
Cytotoxic cross-matching for organ transplantation SIR,-Renal graft survival is improved by optimum or "beneficial" HLA-matching and transplant units are encouraged to exchange kidneys that can safely tolerate up to 48 h of storage at 0-4°C.1 However, the fmal arbiter of organ allocation is not HLA-match but rather cytotoxic cross-match between recipient serum and lymphocytes isolated from donor spleen or lymph node, which are transported with the organ at room temperature.2,3 We recently received a kidney that was said to be a "beneficial match" after positive cross-matching at another centre. Although the organ was potentially viable, the cross-match was impossible because all available lymphocytes were dead. We undertook a survey to assess
