Annotations

In summary, to explain the puzzling observation that cer- tain populations with a high dietary carbohydrate intake have a high tendency to diabetes and coronary artery dis- ease, and others a low tendency, the postulate is made that the amount of exercise could alter the metabolic response of the body to increased dietary carbohydrate and reduce the circulating blood sugar for a given concentration of insulin. Thus exercised individuals would tend to be less “diabetic” and by inference less prone to the development of ischemic heart disease. According to this hypothesis, if a patient at risk of developing ischemic heart disease is given advice to reduce dietary lipid intake, he could be advised to increase intake of carbohydrate, including sucrose, provided he were also advised to take more exercise.

Lionel H. Opie. M.D. Ischemic Heart Disease Laboratory

Department of Medicine University of Cape Town

Cape Town, South Africa

REFERENCES

1.

2.

3.

4.

5.

6.

7.

Yudkin, J., and Roddy, J.: Levels of dietary sucrose in patients with occlusive atherosclerotic disease, Lancet 26, 1964. Bronte-Stewart, B., Keys, A., and Brock, J. F.: Serum- cholesterol, diet, and coronary heart-disease. An inter- racial survey in the Cape Peninsula, Lancet 21103, 1955. Carlson, L. A., and Bbttiger, L. E.: Ischaemic heart dis- ease in relation to fasting values of plasma triglycerides and cholesterol. Stockholm prospective study, Lancet 19365, 1972. Hulley, S. B., Wilson, W. S., Burrows, M., and Nicha- man, M. 2.: Lipid and lipoprotein response of hyper- triglyceridaemic outpatients to a low carbohydrate modification of the A.H.A. fat-controlled diet, Lancet 2:551, 1972. Schlierf, G., and Dorow, E.: Diurnal patterns of triglycerides, free fatty acids, blood sugar, and insulin during carbohydrate-induction in man and their modification by nocturnal suppression of lipolysis, J. Clin. Invest. 52:732, 1973. Himsworth, H. P.: Physiological activation of insulin, Clin. Sci. l:l, 1933. Grey, N., and Kipnis, D. M.: Effect of diet composition on the hyperinsulinemia of obesity, N. Engl. J. Med. 285:827, 1971.

8.

9.

10

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

Jackson, W. P. U., and Keller, P.: Glucose/insulin rela- tionships in a population sample. Hormones 3:361, 1972. West, K. M., and Kalbfleisch, J. M.: Influence of nutri- tional factors on nrevelance of diabetes, Diabetes 20:99, 1971. 1 Cleave, T. L., and Campbell, G. D.: Diabetes, coronary thrombosis and the saccharine disease, 2nd ed.. Bristol, 1969, John Wright, Ltd. Jackson, W. P. U., Goldberg, M. D.. Major, V., and Campbell, G. D.: Vascular and other diabetes-related disorders among Natal Indian diabetics and non- diabetics, S. Afr. Med. J. 44z279, 1970. Wapnick, S., Wicks, A. C. B., Kanengoni, E., and Jones. J. J.: Can diet be responsible for the initial lesion in diabetes? Lancet 2:300. 1972. Chain, E. B., Mansford, K. R. L., and Opie. L. H.: Effects of insulin on the pattern of glucose metabolism in the perfused working and Langendorff heart of normal and insulin-deficient rats, Biochem. J. 115:537, 1969. Neely, J. R., Liebermeister, H.. and Morgan, H. E.: Effect of pressure development on membrane transport of glucose in isolated rat heart. Am. J. Physiol. 212:815. 1967. Holloszy, J. O., and Narahara. H. T.: Studies of tissue permeability X. Changes in permeability to 3- methylglucose associated with contraction of isolated frog muscle, J. Biol. Chem. 240:3493, 1965. Pruett, E. D. R.: Plasma insulin levels during prolonged exercise, in Bernow. B.. and Saltin. B. t&tom: Muscle metabolism during exercise, New York, 1971. Plenum Press, p. 165. Bjsrntrop, P., Fahlen, M., Grimby. G., Gustafson, A., Holm, J., Renstr6m, P., and Schersten, T.: Carbohy- drate and lipid metabolism in middle-aged physically well-trained men, Metabolism 21:1037. 1972. Mann, J. I.. Truswell, A. S., Hendricks. D. A., and Man- ning, E.: Effects on serum-lipids in normal men of reduc- ing dietary sucrose or starch for five months. Lancet 1:870, 1970. Mann. J. I., and Truswell, A. S.: Effects of isocaloric ex- change of dietary sucrose and starch on fasting serum lipids. postprandial insulin secretion and alimentary lipaemia in human subjects, Brit. J. Nutr. 27:395, 1972. Cohen, A. M., and Teitelbaum, A.: Effect of dietary su- crose and starch on oral glucose tolerance and insulin- like activity, Am. J. Physiol. 206:105. 1964. Prior, I. A. M., and Davidson, F.: The epidemiology of diabetes in Polynesians and Europeans in New Zealand and the Pacific, N. Z. Med. J. 65:375. 1966.

Treatment of oat-cell carcinoma of the lung

The results of treatment for cancer of the lung as a whole the results of surgery so depressing that they refer all their have tended to improve steadily over recent years, mainly cases for primary radiotherapy or chemotherapy. Consider- because of earlier diagnosis, elimination of sepsis by anti- able interest has been shown recently in the clinical pre- biotics, improved anaesthetic techniques, and postopera- sentation of oat-cell carcinoma with its ability for hormone tive care. production, and also in new methods of treatment, as of the

All these important factors however have failed to produce various histological varieties of bronchial carcinoma, the oat- any improvement in the results of treatment for oat-cell car- cell variety has always had the worst prognosis. cinema, and some thoracic surgeons and physicians find Most thoracic surgical units will quote cases of oat-cell car-

American Heart Journal 675

Annotations

cinema successfully treated and surviving ten years following surgery, but these cases will almost certainly have been pe- ripheral lesions with negative lymph nodes. Where an oat- cell carcinoma presents in the bronchus, and a positive biop- sy can be obtained then surgery alone is very rarely SUC-

cessful.

In 1955, Bromley and Szur’ tried the effect of combining surgery with preoperative radiotherapy in the hope of im- proving the long term results. They gave their patients an av- erage of 4,700 rads preoperatively on the 250 kv. machine. Unfortunately, this resulted in a 27 per cent complication rate of late bronchopleural fistula and empyema, and the method was therefore abandoned. In their series of 66 pa- tients, there were 11 cases of oat-cell carcinoma, four of whom died soon after operation, and viable cancer cells were present in the remaining seven at death.

As a result of improved techniques and the introduction of cobalt radiotherapy, a comparative trial of surgery and pri- mary radiotherapy for the treatment of oat-cell carcinoma was carried out by the Medical Research Council, and in 1966’they gave a two-year report. There were 71 patients in the surgery series and 73 in the radiotherapy series. At 24

months, 4 per cent of the surgical patients were surviving, and 10 per cent of the radiotherapy patients had survived. These investigators concluded that radical radiotherapy was marginally better treatment than surgery for oat-cell car- cinoma.

In 1969,3 a five-year follow up report on this same trial, showed only one patient alive from the surgical series, and three from the radiotherapy series. Very recently, the IO- year follow up report4 confirmed the improved results with radiotherapy, the three patients still being alive, but none from the surgical series being alive.

In 1968, Lennox and colleagues5 from the London Hospital reported their results in 275 cases of oat-cell carcinoma.

They stated a two-year survival rate of 10.6 per cent for the series, and concluded that surgery still has an important place in the treatment of oat-cell carcinoma. The Medical Research Council then initiated a further trial of cytotoxic chemotherapy as an adjuvant to surgery in carcinoma of the bronchus. They published a two-year report in 1971.6 In a total of 753 patients, 39 were suffering from oat-cell car- cinoma, and they were treated by surgical excision together with either busulfan, cyclophosphamide, or a placebo. After 24 months, three of the 14 patients treated with busulfan were alive, none of the nine patients treated with cyclophos- phamide was alive, and two of the patients treated with a placebo were alive. This interim report suggests that neither of the two cytotoxic drugs used as an adjuvant to surgery im- proved the survival rate.

In a personal series of 97 cases of oat-cell carcinoma oper- ated upon between 1951 and 1966, only nine patients sur- vived for more than two years, eight of whom had lobectomies. One died after 2% years, one after four years, one after five years, and one after 12 years from a coronary infarction. Three patients who had lobectomies are alive and well, one eleven years after operation, and two nine years after operation. The average length of life in the 88 patients who died in under two years from operation, was only 6% months. It was because of these very poor results that the thoracic surgical and radiotherapy departments of the North Middlesex Hospital decided on a trial of surgery combined

with preoperative cobalt irradiation. A simple opposed pair of fields was used to cover the tumor and related mediastinal lymph nodes, the normal field being 15 by 10 or 15 by 12 cm. Seven daily treatments of 250 rads were given to a maximum of 1,750 rads maximum toxic dose. Surgery was carried out the day after treatment was completed, and no reaction in the operative field was noted. As a policy decision, pneumonectomy was performed wherever possible. Twenty- nine patients in this series were operated on between 1966 and 1969, and only one developed a bronchopleural fistula after operation. Twenty-four patients had a pneumonectomy and seven were alive after three years, a survival rate of 24 per cent for the whole series compared with 3 per cent and 7 per cent for the M.R.C. surgery and radiotherapy series respectively. However, of the 24 patients who had the com- bined treatment we are now advocating, 29 per cent were alive and well after three years, and now, four years after the end of the series, six are still alive and well, two of them hav- ing had their operations seven years ago.

We considered these results to be an improvement on any previous form of treatment, and therefore decided to treat a further series of patients suffering from oat-cell carcinoma with 2,500 rads preoperatively. Thirty-one patients were treated in this manner between 1969 and 1973, but the hoped for improvement in length of life has not been ob- tained. It may be that the increased dosage of radiotherapy has interfered with the patient’s own immunity against the disease. As a result of this disappointment, we are now reverting to the original dosage of 1,750 rads.

Histological examination of the specimens in the first series showed that in six of the 24 specimens, the tumor was anaplastic squamous carcinoma. This discrepancy was noticed in the M.R.C.’ trial for surgery and radiotherapy, but to a lesser extent, three specimens out of 37 showing squamous carcinoma, adenocarcinoma, and a mixture of both.

The reason for finding anaplastic squamous carcinoma in the specimen following radiotherapy is not yet certain. It could result from the bronchial biopsy being taken from that small part of a tumor which is indeed oat-cell in nature, while the predominant part of the tumor is squamous in nature. It is well recognized that bronchial tumors may show several different histological patterns in any one tumor. However, the incidence did seem higher than such an ex- planation might support, and therefore the possibility of change from oat-cell to squamous cell appearance as a result of the radiotherapy was considered.

In our second series of cases, where an increased dosage of radiotherapy was used, the squamoid appearance in the specimens has been even more marked. In nearly a third of these cases has this change been shown. This high proportion of histological difference between the bronchial biopsy and specimen appearance makes it very likely that it results from the preoperative irradiation, and this finding has not been previously reported.

It is clear that surgery alone is not the best treatment for oat-cell carcinoma and that some form of combined therapy is likely to be more effective. Cell dissemination by the bloodstream to the liver or brain or suprarenals is such a common end result for a patient with this form of cancer that possibly a triple form of therapy could improve this dismal picture. Preoperative cobalt irradiation could be given to a

676 May, 1975, Vol. 89, No. 5

Annotations

dose not exceeding 2,000 rads so that the surgeon may elect to perform a lobectomy if thought desirable, without the fear of radiation pneumonitis occurring in the remaining lobe, a short course of cytotoxic drugs to cover the operation to destroy any neoplastic cells disseminated at the time of sur- gery, and the resection of the lung tumor which the radiotherapy in itself will not have been sufficient to cure.

Michael Rates, F.R.C.S. Lkpartment of Thoracic Surgery

North Middlesex Hospital London, England

REFERENCES

1. Bromley, L. L., and Szur, L.: Combined radiotherapy and resection for carcinoma of the bronchus: experiences with 66 aatients. Lancet 2937.1965.

and radiotherapy for the primary treatment of small- celled or oat-celled carcinoma of the bronchus, Lancet 2:979, 1966. Medical Research Council: Five year follow-up of the operative treatment with radiotherapy of small-celled or oat-celled carcinoma of the bronchus, Lancet 2:501, 1969. Medical Research Council: Ten year follow-up of the operative treatment with radiotherapy of small-celled or oat-celled carcinoma of the bronchus, Lancet 63. July 14, 1973. Lennox, S. C., Flavell, G., Pollock, D. J., Thompson, V. C., and Wilkins, J. L: Resection for oat cell cancer of the lung, Lancet 2:925, 1968. Medical Research Council: Two year study of cytotoxic chemotherapy as an adjuvant to surgery in carcinoma of the bronchus, Br. Med. J. 2:421, 1971.

2. Medical -Research Council: Comparative trial of surgery

A retrospective case-control study of diiases associated with oral contraceptive use

In 1972, the Boston Collaborative Drug Surveillance Program undertook a large-scale epidemiologic survey to evaluate associations between drug use by ambulatory pa- tients and disease states requiring hospitalization.’ Trained nurse monitors were stationed on general medical and surgi- cal wards in 24 community and university hospitals in the Boston area. A detailed history of all drugs, including oral contraceptives, used prior to hospitalization was obtained from approximately 25,000 consecutively admitted patients aged 20 to 75 years. Drug histories, demographic data, and discharge diagnoses were stored on magnetic tape.

Retrospective case-control analysis was used in the present study. A total of 6,472 females aged 20 to 44 years was monitored. From this group were selected 042 controls, con- sisting of premenopausal women free of any known chronic disease who were hospitalized only for acute illness (trauma, respiratory infections, gastroenteritis, appendicitis) or elec- tive surgery. None of the controls had any disorder which might contraindicate or be caused by oral contraceptive use. Cases also were selected stringently. Only patients having “idiopathic” venous thromboembolism with no apparent pre- disposing cause were included (n = 43). All cases of gallblad-

Table I. Risk ratios and estimated attack rates

der disease were confirmed surgically (n = 212). Cases of benign breast tumor were confirmed histologically (n = 98).

Since oral contraceptive use becomes less common with in- creasing age, risk ratios were age-standardized2 (Table I). The association between venous thromboembolism and oral contraceptive use is highly signitlcant. Duration of use did not influence the risk. The results of other case-control stud- ies are simiIar.3-5 Because idiopathic venous thromboembo- lism is a relatively rare event, the risk may not become ap- parent in prospective studies.6 Enhancement of coagulability induced by oral contraceptives’ probably explains the aesoci- ation with venous thromboemboliem as well as other throm- boembolic disorders.

The association of oral contraceptive use with gallbladder disease also is significant (Table I) and has not been reported previously. The disease tended to develap within the first year of oral contraceptive use. Although the relative risk (2.0) is smaller than for venous thromboembolism Gl.O), the attack rates attributable to oral contraceptives are similar because gallbladder disease is more common in the popula- tion. Women are known to develop gallbladder disorders more frequently than men, particularly during the

Disease Age-standardized

risk ratio Summary

X2 value (d.f. = 1) Significance

level

Yearly attack rate attributable to OC’s per

100,000 GC users

Venous thromboembolism 11 57 p < .OOOl 60 Gallbladder disease 2.0 15.0 p < .OOl 79 Benign breast tumor 0.47 5.4 p = .02 -

American Heart Journal 677