CANCER RESEARCH. This subject falls naturally into two periods divided by the beginning of the present century. From 185o to 190o investigation was on the clinical and anatomical sides and the great work of Virchow between 185o and 186o upon cellular pathology and upon the malignant new growths laid the foundation of our present knowledge concerning cancer. When it is remembered that staining methods for microscopical pur poses were not introduced until about 1872 the accuracy of Virchow's descriptions becomes even more remarkable. Virchow laid great stress upon the importance of chronic irritation in the causation of new growths and in large measure this view still holds the field. Reference is made to it later. The rival theory put for ward by Cohnheim about 188o that new growths arise from em bryological remnants included within the tissues owing to some slight error in development has, at the present time, few adher ents. In the case of certain special varieties of tumour
tomata, cysts), however, it is held to be a sufficient explanation.
As examination of cancer proceeded it be came clear that it is not a single disease but rather a group of diseases having certain features in common. First there came the great division into (I) the carcinomata, growths built up on the type of squamous, columnar or spheroidal epithelium and (2) the sarcomata, growths built on the type of one of the members of the connective-tissue group. To these were added later (3) the endotheliomata, a group of somewhat undetermined characters, which are regarded as being derived from the flattened cells that line lymph spaces or channels or blood-vessels. In this way there has become recognized a long series of malignant growths with more or less defined microscopical characters.
Later it was found that the three main groups mentioned above were insufficient to include certain vari eties of tumour arising in special organs, e.g., muscle, lymphatic glands, testicle, adrenal, sympathetic ganglia, and special terms were applied to new growths originating in these parts. It was shown, further, that in some degree it is possible to correlate clinical with histological features, particularly so far as the pri mary growth is concerned. Thus it is probable that a primary cancer of external skin or of the lining to the alimentary tract between the lips and the lower end of the oesophagus will be a squamous-cell carcinoma, of intestine will be a columnar-cell carcinoma, of bone will be some variety of sarcoma, of cerebral meninges or of pleura will be an endothelioma. These tumours will breed true so that if secondary growths (metastases) are produced they will, within limits, resemble the parent growth in histological characters.
To this 19th century period also belongs the great controversy whether the malignant growths are manifestations of a local or of a constitutional con dition. The controversy is important in that treatment must depend largely upon the view held: if the disease be purely local it should be possible to eradicate it by surgery so long as it is dealt with before it passes from the local condition and be comes generalized; if, on the other hand, it be a manifestation of a constitutional or blood condition, local surgery must be inef fective. The local view received and still receives the greatest amount of assent, but it is becoming more generally accepted, even by those who hold that cancer depends upon local mechanical irritation, that some biochemical change of the tissues is neces sary and that this change may be brought about by conditions affecting the body as a whole.
The remarkable results of bacte riological research about 188o, too, were not without effect, for attempts were made to show that cancer depends upon a micro organism. That micro-organisms were cultivated from new growths is certain, but the varieties were so diverse that, no doubt, they depended upon faulty technique or upon prior and accidental infection of the growth. Moreover, inoculation of these micro-organisms into animals failed to produce new growths, though in some instances (torulae) tumour-like collections of in flammatory cells resulted. It is now generally agreed that no bacillus or micrococcus in the accepted sense of those terms is the cause of cancer.
Again, certain appearances met with in microscopical sections were regarded by their discoverers as being of an animal nature, parasitic and causative of the con dition. It is now agreed that these appearances are due to the inclusion of tissue debris in living cells. It follows from what has been said above, that cancer is not an infectious disease in the sense that tuberculosis, diphtheria, typhus fever and malaria are infectious diseases. Many enquiries were carried out upon the subject of "cancer houses" and "cancer localities." Examples were adduced in which several persons inhabiting a single house or numbers dwelling in the same locality were said to have died of cancer. Careful examination, however, failed to show that they could not be explained by the average age distribution of the population, by improved diagnosis or by errors of random sam pling. While, therefore, there is nothing to show that special cancer houses and localities do not exist, there is no satisfactory proof of their occurrence.
Since the year 190o cancer research has entered upon a new phase largely owing to the fact that modern experimental methods have been adopted. Special labora tories devoted to cancer research were instituted and within a few years were at work at the Imperial Cancer Research fund, The Middlesex Hospital, the Cancer hospital (London), the Christie hospital (Manchester), the Royal Cancer hospital (Glas gow), the Samariterhaus (Heidelberg), the Crocker Foundation, the Memorial hospital, the Rockefeller Institute (New York .City), the Gratwick Foundation (Boston, Mass.). Recently a large institute for cancer research has been opened at Buenos Aires. In addition, associations for the study of cancer have been founded in several countries. These associations differ some what in their aims, but in most instances through their agency statistical and sometimes laboratory investigations are being car ried out. The most important of these associations are the Cancer Sub-committee of the Health section of the League of Nations, which, of course, is international; the Cancer Committee of the Ministry of Health in Great Britain ; the British Empire Cancer Campaign; local committees in Manchester, Liverpool, Birming ham, Leeds; 1'Association Francaise pour l'Etude du Cancer; Komite fur Krebsforschung and similar bodies in Belgium, Hol land, Austria, Switzerland and Japan. It must be understood that the institutions mentioned above are exclusive of numerous bodies such as the Medical Research Council, various universities and teaching hospitals which further cancer research as part of their general activities, and often to a considerable degree, but have no special department devoted to the subject. In 1926 The British Empire Cancer Campaigns founded The Cancer Review in which publications directly or indirectly bearing upon the cancer problems are analysed. In 1928 a somewhat similar journal was issued in France.
In Chicago a laboratory was built and equipped on the most approved plan for investigating the question of heredity and cancer in mice. From three original mice, stocks were raised ultimately numbering many thousands of which the full history of each individual from birth to death was recorded including an account of the autopsy. The experiment has been in progress for some 20 years and by special breeding Miss Maud Slye has produced two strains, all members of which and no mem bers of which, respectively, suffer from new growth. She has also produced familial proclivity to new growths of a special type, e.g., squamous-cell carcinoma, or affecting a special organ, e.g., the liver. From these experiments there can be no doubt that a hereditary factor obtains in cancer, but it is only by controlled work of the kind mentioned and intense inbreeding that its existence can be demonstrated. Even in so segregated a popula tion as that of Gol and Hemsedal, two parishes on the eastern slope of the mountains in the centre of Norway where inter marriage is common, the most that a study of five large cancer families in which 367 deaths had occurred between 1902 and 1921 showed was that the crude mortality rate from cancer for per sons over the age of 35 was 18.2% for these families compared with 12.1% for the total population.
Much time has been spent and many papers have been published on the question whether the incidence of cancer is increasing. It cannot be said that this question has been settled beyond dispute. Increased notification of deaths from cancer has undoubtedly occurred in practically all countries, but how far correction of the annual figures has to be made for increase of population, improved diagnosis, improved standard of health whereby a larger portion of the population reaches the cancer age, improved education and means of trans port whereby a large proportion of the population comes under observation and treatment, it is impossible to say. Nevertheless it is the opinion of most authorities that even if due allowance be made for all these factors there is still evidence of a gradual increase in the incidence of cancer particularly at more advanced ages. The opinion often expressed that cancer affects persons at an earlier age than formerly is apparently without foundation.
Statistical enquiries in various countries have shown that the commonest primary site of the disease differs con siderably. Thus in England and Wales notified deaths from cancer of uterus and of breast are more numerous than from gastric cancer, whereas the reverse is the case in Holland and Italy. This observation has been made the subject of exhaustive enquiry by the Cancer Sub-committee of the Health section of the League of Nations with the result that it is fully substantiated but all endeavours to correlate it with habits of the respective peoples have failed entirely. It is said that the same peculiarity concerns descendants of the same nationalities when they have emigrated to another country and this point is receiving attention at the present time.
Another useful statistical enquiry con cerns the natural duration of the untreated disease from alleged onset to death. Papers have been published giving the informa tion derived from four different institutions in Great Britain. These have been collected and analysed statistically by the Can cer Committee of the Ministry of Health and present a base line against which all forms of treatment can be measured.
Enquiries in all parts of the world have shown that cancer affects all races of mankind and examina tion of lower animals has demonstrated its occurrence in them also. It may not be, and certainly in the case of lower animals is not the fact, that all species and varieties are affected with equal frequency. Thus the mouse is the subject of cancer more frequently than the rat, and the rabbit and guinea-pig are far less frequently affected than either. Inasmuch as dogs, cats, horses and cattle are relatively more frequently attacked by can cer it is considered that it is a disease of domestication. Similarly there appears with great probability to be a higher incidence of cancer in the more civilized races of mankind.
The observation that cancer affects the lower animals has rendered experimental work possible. The fact was first shown over 4o years ago by Hanau who successfully transplanted a squamous-cell carcinoma from the vulva of a rat into the peritoneal cavity of other rats. Ten years later Morau succeeded in transmitting a mammary adenocarcinoina from a white mouse to other white mice. For many years the indications afforded by these experiments were not followed up, in part because of a doubt how far the analogy between growths in these lower animals and cancer affecting man holds good. Extensive research, however, carried out mainly by the Imperial Cancer Research fund, proved clearly their essential similarity, and from that time much knowledge has accrued from the experiments on malignant tumours of the mouse and rat. Amongst the conclusions reached was that on the rigorous specificity exhibited by growths. Thus a tumour of the mouse will not grow if inoculated into the rat or vice versa. Under spe cial conditions temporary growth may occur, but these do not invalidate the truth of the general statement.
As might be expected much work has been done on the question of susceptibility and resis tance to transplanted grafts in the hope that it might throw light upon treatment in man. Important differences were shown to obtain between spontaneous growths in respect of the ease or difficulty with which they can be transplanted into other animals of the same species. In some cases grafts take in nearly i00% of experimental animals, in others failure is consistent, even with the greatest care. It was found, however, that inoculation of a graft beneath the skin of the animal bearing the primary tumour (autologous grafting) is almost always successful. This indicates some peculiarity of the animal bearing a spontaneous tumour, but so far the difference has eluded explanation.
It has been suggested that there is a larger amount of potassium in the blood and tissues of an animal bear ing a spontaneous tumour. Supporting this view are the observa tions (a) that the blood and tissues of persons suffering from cancer contain more potassium than those of persons suffering from non-malignant diseases and (b) that if the potassium content of the blood of mice be raised by feeding them with potassium metaphosphate, transplanted grafts of a mouse carcinoma take in a larger proportion of cases, appear earlier and grow at a more rapid rate.
An important observation, repeatedly confirmed, is that if an animal spontaneously recover from a transplanted tumour it is immune to subsequent inoculations with the same tumour. This has been made the basis of innumerable attempts on the curative side, the most important of which consists in removal of a portion of the tumour, irradiation to a degree just sufficient to prevent growth of the cells on re-inoculation and the introduction of the irradiated mass beneath the skin of the original patient. In experiments on rats the method has been shown to confer a large degree of resistance against growth of inoculated grafts, though it is not so effective against established tumours. It has been found, also, that introduction into liver or spleen is more effective than beneath the skin. In man the results are not conclusive.
In all experiments upon resistance and susceptibility to cancer a great subject of difference amongst workers lies in their view as to the essential factor concerned. Some investigators hold that it is the fluids of the body that are of importance, the cellu lar elements being subsidiary. For others the cells, and particu larly the lymphocytes, are the prime factor in resistance ; if the particular line of treatment adopted be associated with accumu lation of lymphocytes locally, resistance is high ; if lymphocytes be few or absent, resistance is low. Experiments can be adduced supporting or refuting either contention but if it be allowable to use the analogy of immunity and susceptibility to bacterial disease it may well be that tissue fluids and cells take varying parts according to circumstances as yet hardly understood.
Here it is convenient to consider attempts at treatment of cancer by various sera. Influenced by a belief in the microbial causation of cancer and the efficacy of antisera produced against such a disease as diphtheria, earlier workers had endeavoured without success to treat the disease by injection of ascitic or other serous fluids derived from cancer patients. More recently attempts have been made in the laboratory to produce an antiserum by the usual methods and test its efficiency against cancer cells growing in vitro. The growing cancer cells were found to be killed almost instantaneously by this antiserum whereas normal cells were unaffected and the method was applied in vivo, with the addition that contact between the antiserum and the cancer cells was rendered more intimate and prolonged by combining venous and lymphatic obstruction with introduction of the antiserum. Grafts were inoculated into the hind feet of rats and when they had reached a certain size the antiserum was introduced in the neighbourhood of one of the growths and was held in position to a large degree by constriction of the thigh. In a large proportion of cases the growth in this foot underwent absorption and not only so but at a little later date the growth in the other foot also disappeared. It would seem that the anti serum led to absorption of the growth to which it was locally applied and that in accordance with the general principle that absorption of a cancerous mass in an animal is associated with increased resistance to the same type of growth, absorption of the first growth in the treated foot led to absorption of the second growth in the untreated foot.
The main criticisms of these important observa tions are (I) that the growth treated was of the transplanted and not of the spontaneous variety, (2) that the foot is by reason of its small size, large amount of bone and tendon, and smallness of its blood-vessels a region naturally somewhat unfavourable to growth of a transplanted tumour and (3) that the constriction, which, apparently, is essential to success, is itself an abnormal condition and might well turn the scale against a growth that was struggling for existence or at least was not growing freely. Workers with these animal tumours know well how widely the behaviour of grafts varies even under conditions that are appar ently identical. Although the experiment is of great interest and full of suggestion it must not be assumed at present that it paves the way to an analogous treatment of cancer in man.
This method was popularized by Carrel. By its means it is possible to determine the action of various agents upon living cancer cells under controllable con ditions. The technique itself is delicate. Originally the portions of living tissue were cultured in plasma, but the method has been simplified by adoption of a modified Ringer's solution with the addition of embryonic tissue juice. Subcultures must be made every two or three days, but under suitable conditions tissue can be kept alive and growing for prolonged periods. In 1922 the description was given of a ten-year old strain of fibroblasts origi nally obtained from the heart of a chick embryo and then in the I 86oth generation; increase in size under the artificial conditions was as rapid as at first. Besides fibroblasts, large mononuclear cells and cartilage cells, each in pure culture, cardiac muscle from chick, duck, frog, etc., tissue from kidney, thyroid and from various animal tumours has been cultivated. It has been shown that foetal tissues are capable of growing in vitro 72 hours after death of the animal and in 1924 evidence was adduced that spleen, liver, kidney, ovary, lung and cornea from adult animals may develop in vitro many hours after death. The development very likely proceeds from surviving cells perhaps activated by the auto lytic products of the dead ones. A remarkable point was shown in connection with in vitro cultures of kidney. It was possible to obtain cultures of fibroblasts or of renal cells and in each instance growth took place in all directions with production of a solid mass. But if fibroblasts were introduced into a mass already containing proliferated renal cells a tubulation occurred that recalled the microscopical structure of the kidney (see DEDIF
