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PARENTERAL FEEDING AND CANCER
999 IN-VIVO EFFECTS OF DIAGNOSTIC ULTRASOUND
Letters
to
the Editor
PARENTERAL FEEDING AND CANCER
SiR,—In their hypothesis about a possible relationship between dietary intake, immune function, and resistance to infection Murray and Murray’ cite the infectious hazards associated with parenteral hyperalimentation. Their hypothesis could be applied to cancer as well as to infection, and it is possible that parenteral nutrition has a stimulating effect on cancer also.
Dietary manipulation affects both cell-mediated immunity (c.M.i.) and the genesis of tumours in mice. Calorie restrictionI enhances C.M.!. and inhibits the appearance of spontaneouS2 and virally or chemically induced tumours.3 Increased calorie intake by dietary fat enrichment increases the incidence of many mouse tumours.3 Mild, chronic protein deprivation enhances C.M.!. while severe deficiency depresses it,4 but the effects of protein restriction on tumorigenesis are less clear cut. Inhibitory effects of dietary restriction on established tumours are generally seen only when the diet is barely sufficient to sustain life.3 On the other hand, there is good evidence that parenteral nutrition of rats bearing transplanted hepatoma leads to
acceleration of tumour growth.S
.
In man, direct evidence on the effects of mild dietary variation on c.m.i. and tumorigenesis and tumour growth is hard to obtain, but severe malnutrition is associated with depressed c.M.i. The anorexia of cancer may represent an attempt to boost host defences, but these are massively overwhelmed by the time the tumour is clinically obvious. Unless the tumour is removed the anorectic stimulus persists, and a vicious circle is set up with a starving patient harbouring a growing tumour whose altered carbohydrate metabolism6 may give it a selective advantage in such a situation. Oral force-feeding of cancer patients at this stage of the disease has probably resulted in acceleration of the disease.’ In the light of this evidence that hyperalimentation may accelerate tumour growth in both animals and man, the use of
parenteral hyperalimentation as an adjunct to cancer therapy, as is being increasingly advocated,8 should be viewed with caution. Unless tumour bulk can be reliably decreased, tumour growth may be accelerated by the treatment in some patients. Tumour ablation may often be achieved surgically, but chemotherapy of solid tumours remains unpredictable in its effect. Parenteral hyperalimentation should not be used routinely in patients with cancer until we have controlled evidence that it improves the efficacy of chemotherapy or improves c.M.i. in the absence of tumour regression. We need to know more about the metabolic state of patients with advanced cancer, their response to parenteral hyperalimentation in terms of changes in body composition, hormone
profile, and hormone-sensitivity, and the relationship of these to indices of C.M.!. and tumour status. Until this evidence is available we should not routinely submit patients to a treatment which may be not only inappropriate but also harmful. Oncology Section, Clinical Research Centre Harrow, Middlesex HA1 3UJ
M. BURKE A. E. KARK
SIR,-You have lately published reports on the biological effects of low-level ultrasound on in-vitro systems (such as D.N.A. solutions) and their possible in vivo significance.1-4 A pattern seems to be emerging for the in-vivo effects of diagnostic ultrasound on nervous tissue. Over a decade ago, Tsutsumi and coworkers5 (as lately noted by Hussey6) reported on the effects of the ultrasonic output of echoencephalography on nervous tissue in dogs. Pulsed ultrasound (centre frequency 2 MHz, pulse duration 4 fLs, pulse-repetition frequency 65 Hz, "mean" intensity 1.5 mW/ cm2) from a single probe placed over the intact scalp and skull reversibly increased glutamic oxaloacetic transaminase (G.O.T.) activity in cerebrospinal fluid (c.s.F.), while serum activity remained normal. G.O.T. activity in dogs irradiated for more than 9 h had reached a peak by 6 h after irradiation but then fell to normal 5 days later. Raised G.O.T. concentrations in c.s.F. are seen in patients with cerebral infarction or convulsions, being attributed to escape of cellular G.o.T. rather than a defect in the blood-brain barrier.’ Hu and Ulrich exposed adult squirrel monkeys through the intact scalp and skull to a pulsed ultrasound from a diagnostic unit while electroencephalograms (E.E.G.S) were obtained from implanted electrodes. Evoked E.E.G. responses appeared immediately upon start of sonication but disappeared after 3 min exposure. (The pulses had a centre frequency of 2-25 MHz, duration 2 us, repetition frequency 1 kHz, and intensity 3 mW/cm2). Similar effects were found for therapeutic levels (0-9-2 W/cm2) of continuous-wave ultrasound. Because the skull is highly absorbing, the intracranical sound levels would be expected to be substantially lower than the reported exposure values. Besides this enzyme and E.E.G. work, there are several studies of behaviour in rats. Murai et al. exposed albino rats in utero on the ninth day of gestation to 5 h of 2-2 MHz, 2 mW/cm,l ultrasound (apparently continuous wave) and found that the postnatal grasp-reflex response was significantly delayed compared with both the sham-irradiated and untreated control animals. Later work by Murai et al. 10 on the same animals revealed significantly increased emotional responses (viz., increased vocalisation in response to handling and increased avoidance of electroshock). Finally, Sikov et al.11 found that rats sonicated at 15 days of gestation with 0.93 MHz continuous wave (apparently) ultrasound with intensities as low as 10 mW/cm2 showed a general delay in neuromuscular development. Thus several independent groups have found that diagnostic ultrasound produces biochemical, E.E.G., and behavioural effects connected with C.N.S. tissue in mammals. We cannot yet comment on the significance of delayed or reversible biological effects for the safety of diagnostic ultrasound; we believe that more work is needed on the effects of low-level ultrasound on nervous tissue, with particular emphasis on functional as opposed to anatomical lesions. Division of Biological Effects, Bureau of Radiological Health, Food and Drug Administration, Rockville, Maryland 20857, U.S.A.
1. 2. 3. 4.
H. M. FROST M. E. STRATMEYER
Galperin-Lemaitre, H., Kirsch-Volders, M., Levi, S. Lancet, 1975, , 662. Thacker, J. ibid. p. 770. Coakley, W. T., Dunn, F. ibid. p. 1037. Prasad, N., Prasad, R., Bushong, S. C., North, L. B., Rhea, E. ibid. 1976, , 1181.
5. Tsutsumi, Y.,
1 Murray, M. J., Murray, A. B. Lancet, 1977, , 123. 2 Fernandes, G., Yunis, E. J., Good, R. A. Nature, 1976, 263,
504.
3 Tannenbaum, A., Silverstone, H. m Advances m Cancer Research (edited by J. P. Greenstein, and A. Haddow); p. 492 New York, 1953. 4. Jose, D. G., Stutman, O., Good, R. A. Nature, 1973, 241, 57. 5. Cameron, I. L., Pavlat, W. A. J. natn. Canc. inst. 1976, 56, 597. 6 Weber, G. New Engl. J. Med. 1977, 296, 541. 7 erepka, A. R., Waterhouse, L. Am. J. Med. 1956, 20, 225. 8. Copeland, E. M., Dudrick, S. J. Sem. Oncol. 1975, 2, 329.
Sano, K., Kuwabara, T., Takakura, K., Hayakawa, I., Suzuki, T., Katanuma, M. Med. Electron. biol. Eng. 1964, 2, 21. 6. Hussey, M. Diagnostic Ultrasound; p. 230. Glasgow, 1975. 7. Frankel, S., Reitman, S., Sonnenwirth, A. C. (editors) Gradwohl’s Clinical Laboratory Methods and Diagnosis; vol. II, p. 173. St Louis, 1970. 8. Hu, J H., Ulrich W. D. Aviation, Space, envir. Med. 1976, 47, 640. 9 Murai, N., Hoshi, K., Nakamura, T. Tohoku J. exp. Med. 1975, 116, 17. 10. Murai, N., Hoshi, K., Chun-hua Kang, Suzuki, M. ibid 1975, 117, 225. 11. Sikov, M. R., Hildebrand, B. P., Stearns, J. D. 1st Meeting of World Federation
for Ultrasound in Medicine and Biology, held in San Francisco paper 1745 (work in progress).
August, 1976;
in
Letters
to
the Editor
PARENTERAL FEEDING AND CANCER
SiR,—In their hypothesis about a possible relationship between dietary intake, immune function, and resistance to infection Murray and Murray’ cite the infectious hazards associated with parenteral hyperalimentation. Their hypothesis could be applied to cancer as well as to infection, and it is possible that parenteral nutrition has a stimulating effect on cancer also.
Dietary manipulation affects both cell-mediated immunity (c.M.i.) and the genesis of tumours in mice. Calorie restrictionI enhances C.M.!. and inhibits the appearance of spontaneouS2 and virally or chemically induced tumours.3 Increased calorie intake by dietary fat enrichment increases the incidence of many mouse tumours.3 Mild, chronic protein deprivation enhances C.M.!. while severe deficiency depresses it,4 but the effects of protein restriction on tumorigenesis are less clear cut. Inhibitory effects of dietary restriction on established tumours are generally seen only when the diet is barely sufficient to sustain life.3 On the other hand, there is good evidence that parenteral nutrition of rats bearing transplanted hepatoma leads to
acceleration of tumour growth.S
.
In man, direct evidence on the effects of mild dietary variation on c.m.i. and tumorigenesis and tumour growth is hard to obtain, but severe malnutrition is associated with depressed c.M.i. The anorexia of cancer may represent an attempt to boost host defences, but these are massively overwhelmed by the time the tumour is clinically obvious. Unless the tumour is removed the anorectic stimulus persists, and a vicious circle is set up with a starving patient harbouring a growing tumour whose altered carbohydrate metabolism6 may give it a selective advantage in such a situation. Oral force-feeding of cancer patients at this stage of the disease has probably resulted in acceleration of the disease.’ In the light of this evidence that hyperalimentation may accelerate tumour growth in both animals and man, the use of
parenteral hyperalimentation as an adjunct to cancer therapy, as is being increasingly advocated,8 should be viewed with caution. Unless tumour bulk can be reliably decreased, tumour growth may be accelerated by the treatment in some patients. Tumour ablation may often be achieved surgically, but chemotherapy of solid tumours remains unpredictable in its effect. Parenteral hyperalimentation should not be used routinely in patients with cancer until we have controlled evidence that it improves the efficacy of chemotherapy or improves c.M.i. in the absence of tumour regression. We need to know more about the metabolic state of patients with advanced cancer, their response to parenteral hyperalimentation in terms of changes in body composition, hormone
profile, and hormone-sensitivity, and the relationship of these to indices of C.M.!. and tumour status. Until this evidence is available we should not routinely submit patients to a treatment which may be not only inappropriate but also harmful. Oncology Section, Clinical Research Centre Harrow, Middlesex HA1 3UJ
M. BURKE A. E. KARK
SIR,-You have lately published reports on the biological effects of low-level ultrasound on in-vitro systems (such as D.N.A. solutions) and their possible in vivo significance.1-4 A pattern seems to be emerging for the in-vivo effects of diagnostic ultrasound on nervous tissue. Over a decade ago, Tsutsumi and coworkers5 (as lately noted by Hussey6) reported on the effects of the ultrasonic output of echoencephalography on nervous tissue in dogs. Pulsed ultrasound (centre frequency 2 MHz, pulse duration 4 fLs, pulse-repetition frequency 65 Hz, "mean" intensity 1.5 mW/ cm2) from a single probe placed over the intact scalp and skull reversibly increased glutamic oxaloacetic transaminase (G.O.T.) activity in cerebrospinal fluid (c.s.F.), while serum activity remained normal. G.O.T. activity in dogs irradiated for more than 9 h had reached a peak by 6 h after irradiation but then fell to normal 5 days later. Raised G.O.T. concentrations in c.s.F. are seen in patients with cerebral infarction or convulsions, being attributed to escape of cellular G.o.T. rather than a defect in the blood-brain barrier.’ Hu and Ulrich exposed adult squirrel monkeys through the intact scalp and skull to a pulsed ultrasound from a diagnostic unit while electroencephalograms (E.E.G.S) were obtained from implanted electrodes. Evoked E.E.G. responses appeared immediately upon start of sonication but disappeared after 3 min exposure. (The pulses had a centre frequency of 2-25 MHz, duration 2 us, repetition frequency 1 kHz, and intensity 3 mW/cm2). Similar effects were found for therapeutic levels (0-9-2 W/cm2) of continuous-wave ultrasound. Because the skull is highly absorbing, the intracranical sound levels would be expected to be substantially lower than the reported exposure values. Besides this enzyme and E.E.G. work, there are several studies of behaviour in rats. Murai et al. exposed albino rats in utero on the ninth day of gestation to 5 h of 2-2 MHz, 2 mW/cm,l ultrasound (apparently continuous wave) and found that the postnatal grasp-reflex response was significantly delayed compared with both the sham-irradiated and untreated control animals. Later work by Murai et al. 10 on the same animals revealed significantly increased emotional responses (viz., increased vocalisation in response to handling and increased avoidance of electroshock). Finally, Sikov et al.11 found that rats sonicated at 15 days of gestation with 0.93 MHz continuous wave (apparently) ultrasound with intensities as low as 10 mW/cm2 showed a general delay in neuromuscular development. Thus several independent groups have found that diagnostic ultrasound produces biochemical, E.E.G., and behavioural effects connected with C.N.S. tissue in mammals. We cannot yet comment on the significance of delayed or reversible biological effects for the safety of diagnostic ultrasound; we believe that more work is needed on the effects of low-level ultrasound on nervous tissue, with particular emphasis on functional as opposed to anatomical lesions. Division of Biological Effects, Bureau of Radiological Health, Food and Drug Administration, Rockville, Maryland 20857, U.S.A.
1. 2. 3. 4.
H. M. FROST M. E. STRATMEYER
Galperin-Lemaitre, H., Kirsch-Volders, M., Levi, S. Lancet, 1975, , 662. Thacker, J. ibid. p. 770. Coakley, W. T., Dunn, F. ibid. p. 1037. Prasad, N., Prasad, R., Bushong, S. C., North, L. B., Rhea, E. ibid. 1976, , 1181.
5. Tsutsumi, Y.,
1 Murray, M. J., Murray, A. B. Lancet, 1977, , 123. 2 Fernandes, G., Yunis, E. J., Good, R. A. Nature, 1976, 263,
504.
3 Tannenbaum, A., Silverstone, H. m Advances m Cancer Research (edited by J. P. Greenstein, and A. Haddow); p. 492 New York, 1953. 4. Jose, D. G., Stutman, O., Good, R. A. Nature, 1973, 241, 57. 5. Cameron, I. L., Pavlat, W. A. J. natn. Canc. inst. 1976, 56, 597. 6 Weber, G. New Engl. J. Med. 1977, 296, 541. 7 erepka, A. R., Waterhouse, L. Am. J. Med. 1956, 20, 225. 8. Copeland, E. M., Dudrick, S. J. Sem. Oncol. 1975, 2, 329.
Sano, K., Kuwabara, T., Takakura, K., Hayakawa, I., Suzuki, T., Katanuma, M. Med. Electron. biol. Eng. 1964, 2, 21. 6. Hussey, M. Diagnostic Ultrasound; p. 230. Glasgow, 1975. 7. Frankel, S., Reitman, S., Sonnenwirth, A. C. (editors) Gradwohl’s Clinical Laboratory Methods and Diagnosis; vol. II, p. 173. St Louis, 1970. 8. Hu, J H., Ulrich W. D. Aviation, Space, envir. Med. 1976, 47, 640. 9 Murai, N., Hoshi, K., Nakamura, T. Tohoku J. exp. Med. 1975, 116, 17. 10. Murai, N., Hoshi, K., Chun-hua Kang, Suzuki, M. ibid 1975, 117, 225. 11. Sikov, M. R., Hildebrand, B. P., Stearns, J. D. 1st Meeting of World Federation
for Ultrasound in Medicine and Biology, held in San Francisco paper 1745 (work in progress).
August, 1976;
in