CANCER RESEARCH

this subject falls naturally into two periods divided by the beginning of the present century. from 1850 to 1900 investigation was on the clinical and anatom- ical sides and the great work of virchow between 1850 and 1860 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 purposes 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 ficld. reference is made to it later. the rival theory put forward by cohnheim about 1880 that new growths arise from embryological remnants included within the tissucs owing to some slight error in development has, at the present time, few adherents. in the case of certain special varieties of tumour (teratomata, cysts), however, it is held to be a sufficient explanation. main divisions.—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 (1) 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 mem- bers 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 flat- tened cells that line lymph spaces or channels or blood-vessels. in this way there has become recognised a long series of malig- nant growths with more or less defined microscopical characters. special divisions.—later it was found. that the three main groups mentioned above were insufficient to include certain varieties of tumour arising in special organs, e.g., muscle, lym- phatic 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 primary growth is concerned. thus it is probable that a primary cancer of external skin or of the lining to the ali- mentary tract between the lips and the lower end of the oesopha- gus 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. local or constitutional origin.—to this 1oth-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 local in its origin it will be possible to eradicate it by surgery so long as it is dealt with before it passes from the local condition and be- comes generalised. if, on the other hand it be a manifestation of a constitutional or blood condition, local surgery must be ineffective. the local view received and still receives the great- est amount of assent, but it is becoming more generally accepted, even by those who hold that cancer depends upon local mechan- ical irritation, that some biochemical change of the tissues is necessary and that this change may be brought about by con- ditions affecting the body as a whole. bacteriological results —the remarkable results of bacteri- ological research about 1880, 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 cancer research these micro-organisms into animals failed to produce new growths, though in some instances tumour-like collections of inflamma- tory cells (torulae) resulted. it is now generally agreed that no bacillus or micrococcus in the accepted sense of those terms is the cause of cancer. cancer not “infectious.” —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 sampling. while, therefore, there is nothing to show that special cancer houses and localities do not exist, there is no satis- factory proof of their occurrence. the present century.—since the year 1900 cancer research has entered upon a new phase largely owing to the fact that modern experimental methods have been adopted. special laboratories devoted to cancer research were instituted and within a few years were at work at the imperial cancer research fund, the mid- dlesex elospital, the cancer hospital (london), the christie hospital (manchester), the royal cancer hospital (glasgow), 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 carried 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 com- mittee of the ministry of wealth in great britain; the british empire cancer campaign; local committees in manchester, liverpool, birmingham, leeds; vassociation francaise pour i'etude du cancer; komite fiir krebsforschung and similar bodies in belgium, holland, austria and japan. it must be understood that the institutions and associations 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. one of the most recent decisions of the british empire cancer campaign is the foundation of a journal of cancer abstracts and reviews in which publications directly or indirectly bearing upon the cancer problem will be analysed. passing now to consideration of the results obtained by this mass of workers on cancer during the first quarter of the 2oth century it may be said that much of the labour has been spent on clearing the ground. heredity in cancer.—in chicago a laboratory was built and equipped on the most approved plan for investigating the ques- tion 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 members 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 cancer research that its existence can be demonstrated. f.ven in so segregated a population as that of gol and hemsedal, two parishes on the eastern slope of the mountains in the centre of norway where intermarriage 1s common, the most that a study of s large cancer families in which 367 deaths had occurred between 1902 and 1921 showed was that the crude mortality rate from cancer for persons over the age of 35 was 18-2°4 for these families compared with 12-1 ° for the total population. other stufistical ienquiries—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, im- proved standard of health whereby a larger portion of the popula- tion reaches the cancer age, improved education and means of transport whereby a larger proportion of the population comes under observation and treatment, it is impossible to say. never- theless it is the optnion 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 earlicr age than formerly is apparently without sound foundation. primary sites.—statistical enquiries in various countrics have shown that the commonest primary site of the disease differs considerably. 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 has 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. duration of cancer.—another useful statistical enquiry con- cerns the natural duration of the untreated disease from reputed 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 cancer committee of the ministry of health and present a base line against which all forms of treatment can be measured. distribution by races—enquiries in all parts of the world have shown that cancer affects all races of mankind and ex- amination 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 cancer 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 civilised races of mankind. experimental transmission by grafts —the observation that cancer affects the lower animals has rendered experimental work possible. the fact was first shown 40 years ago by htanau 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 adeno- carcinoma from a white mouse to other white mice. for many years the indications afforded by these experiments were not fol- lowed 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 ot3 specificity exhibited by growths. thus a tumour of the mouse will not grow if inoculated into the rat or vice versa. under special conditions temporary growth may occur in those cross inoculations, but these exceptional cases do not invalidate the truth of the general statement. susceptibility and resistance-—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 100% 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 cluded explanation. blood content.—it has been suggested that there is a larger amount of potassium in the blood and tissues of an animal bearing a spontaneous tumour. supporting this view are the observations (a) that the blood and tissues of persons suffering from cancer contain more potassium than those of persons suffering from non-malignant diseases and (4) that if the potas- slum content of the blood of mice be raised by feeding them with potassium metaphosphate, transplanted grafts of a mouse car- cinoma take in a larger preportion of cases, appear earlier and grow at a more rapid rate. immunity.—an important observation, repeatedly con- firmed, is that if an animal spontaneously recover from a trans- planted 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 con- sists in removal of a portion of the tumour, irradiation to a de- gree just sufficient to prevent growth of the cells on re-inoculation and then introduction of the irradiated mass beneath the skin of the original patient. in experiments on rats the method has been shown to confer a good degree of resistance against growth of inoculated grafts, though it is not so effective against estab- lished tumours. it has been found, also, that the tissue into which the irraciated mass is introduced is not without impor- tance, introduction into liver or spleen being more effective than beneath the skin. subcutaneously the method has been applied in man but 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 investi- gators hold that it is the fluids of the body that are of im- portance, the cellular elements being subsidiary. tor others the cells, and particularly the lymphocytes, are the prime factor in resistance; if the particular line of treatment adopted be associated with accumulation of lymphocytes locally, resistance is high; if lymphocytes be few or absent, resistance is low. ex- periments can be adduced supporting or refuting either conten- tion but if it be allowable to use the analogy of immunity and susceptibility to bacterial disease it may well be that tissue fluids and tissue cells take varying parts in the process according to circumstances as yet hardly understood. serum treatmeni.—lere 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, earlicr workers had endeavoured without success to treat the disease by in- jection of ascitic or other serous fluids derived from cancer pa- tients. 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 514 obstruction with introduction of the antiserum. grafts were in- oculated 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 antiserum 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. criticisms.—the main criticisms of these important obser- vations are (1) 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 smaliness 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. tissue culture in vitro.—this method was popularized by car- rel. by its means it is possible to determine the action of various agents under controllable conditions. 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 originally obtained from the heart of a chick embryo and then in the 186o0th generation; in- crease 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 autolytic products of the dead ones. a remarkable point was shown in connection with i# 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. this experi- ment may be correlated with the observation that in the growth of a transplanted tumour graft the stroma is furnished by the host and therefore that the microscopical appearance of the growth is determined largely by the fibrous tissue. experiments on aettology—the frequency with which cancer of the tongue is associated with a jagged tooth or an ill-fitting denture, cancer of the lip with smoking of clay pipes, the oc- currence of cancer of the skin in workers with paraftin and tar, of soot cancer in chimneysweeps, arsenic cancer, kangri cancer amongst the kashmiri users of the kangri basket, cancer of the cheek amongst betel-nut chewers, cancer of the bladder in workers with anilin and around the parasitic ova in persons in- fected with bilharzia, are examples where irritation caused by a mechanical agent seems to bear a causal relation to the cancer. x-ray cancer.—of recent years x-ray cancer has been added to the list, and there is reason to believe that cancer of the skin may result from prolonged exposure to the gamma rays of ra- cancer research dium. lazarus barlow has found minute quantities of radium to exist in a large proportion of cancers examined for the purpose, and produced in the gall bladders of rabbits a condition indis- tinguishable from cancer by introducing into the gall bladder human gallstones into which small quantities of radium had been introduced artificially. irritation and cancer.—subsequently leitch produced cancer of the gall bladder in guinea-pigs by the use of gallstones or of small pebbles. the exact relation of the chronic irritation to the subsequent cancer is unknown, and there is no doubt that in an even larger number of cases chronic irritation occurs without any subsequent development of cancer. in most instances the chronic irritation must persist over a number of years and the actual cancerous condition is preceded by the formation of warty outgrowths and other local manifestations of cell destruc- tion accompanied by cell proliferation. tur cancer.—in the case of tar a cancerous condition has been produced in mice and rabbits, but hitherto never in rats, by repeated local painting with coal tar. the cancer is of the squamous variety and runs a normal course. under the same conditions of painting the length of time before cancer super- venes varies between 3 and 18 months for individual mice. an observation that may have important bearings is that when growth has been produced in one part of the body by means of tar it is impossible to produce another cancer elsewhere by the same means. this is complementary to the experience derived from transplanted cancer in which resistance to one variety of new growth may coincide with susceptibility to another variety. strenuous efforts have been made to isolate the carcinogenic principle in tar and crude parafiin oils but without success. on the other hand “ tars ” prepared from isoprene and acetylene by distilling at temperatures between 700° and 900° c. were some of the most effective cancer producers yet known. the same was true for “ tars” produced by the same temperatures on various tissue derivatives. artifictal infection.—fibiger succeeded in producing cancer of the stomach and tongue in rats by feeding them with cock- roaches infected with spiroptera neoplastica, and bullock and his collaborators produced a malignant condition in rats by feed- ing them with taenia crassicollis, a tapeworm infesting the cat. the sarcomatous growth occurred round the cysts formed in the liver by the tapeworm and was produced within a few weeks. the rous experiments —in the attempt to find some com- mon factor behind these widely diverse conditions antecedent to cancer, attention was directed towards observations made by peyton rous on a chicken sarcoma that could be transmitted by inoculating with dead cells or, in the absence of cells, by a tumour extract that had passed through a berkefeld filter. subsequently rous found two other varieties of sarcoma in hens which could be transmitted by filtered tumour juice. in each of the three in- stances the special characters of the original growth were re- peated in the experimental tumours, he and his collaborators brought forward strong evidence that the filterable agent was a living but extremely small microbe. gye’s two factors—although all attempts ‘te discover a filterable virus in mammalian cancer had failed and successful transplantation can only be carried out by means of living cells, it occurred to gye that two factors might be concerned in the production of one of these chicken sarcomata, viz., a filterable virus and a specific factor derived from the animal. by special means he separated the two and found that either alone was insufficient to produce a tumour but in conjunction they were effective. he then applied these results to four standard malig- nant tumours in rats and mice and one human mammary cancer with the result that he obtained from all but one mouse tumour a factor he regards as almost certainly a filterable virus which can replace the virus of the rous tumour in the production of a chicken sarcoma. the failure to transmit mammalian growths in the same fashion as the rous chicken sarcoma he ascribes to the more rapid destruction of the mammalian specific factor, prob- ably by oxidation. for the last-mentioned conclusion he has brought forward experimental evidence. caneva—cannes, conference of these researches, which are still in progress, have led gye to look on cancer—using the term in its widest sense—as a specific disease caused by a virus (or group of viruses). under experimental conditions the virus alone is ineffective; a second specific factor ob- tained from tumour extracts ruptures the cell defences and enables the virus to infect. under natural conditions continued irritation of tissues sets up a state under which tufection can occur. the filtered material isolated by gye and supposed to contain a virus, after subculture, was examined photographically by barnard with special optical apparatus, ultraviolet light and, where necessary, quartz in place of glass. barnard obtained and has published appearances of a particular agent in the culture medium which he and gye regard as the virus under discussion. filterable virus.—this work, without doubt, is of great im- portance but caution must be exercised in its interpretation. the occurrence of unsuspected minute bodies in what are re- garded as normal animals has been shown in monkeys, rabbits and guinea-pigs, e.g., in the work on lethargic encephalitis, and rivers and pearce while investigating varicella found in rabbits a filterable virus which, at first thought by them to be that of varicella, proved ultimately to be indigenous in rabbits. ‘this possibility must be climinated before gye’s observations can be taken to prove that his filterable virus came from the sarcoma as distinguished from the chicken. morcover rivers and pearce also found that rabbits bearing intratesticular growths of a transplantable tumour, first discovered in syphilised rabbits, are immune to their rabbit filterable virus, though the virus infects the growth itself and multiplies therein. specific factors.—it may be that filterable viruses peculiar to certain animals exist but are unable to produce tumours until some “ specific factor ” is present, or that a filterable virus pecul- lar to new growths exists but also requires the presence of a spe- cific factor, or it may be that the filterable virus inhabits the tumour and is, in a sense, accidental. it is clear that some stimulus for the increased and atypical multiplication of cells which characterises the new growths is necessary but it seems that much more work is needed before it can be accepted that a filterable virus is aetiologically connected with all varieties of malignant new growth. for the sarcomata—with their many histological and clinical resemblances to infective and inflam- matory conditions—causation by a particular filterable virus is more easily acceptable and it will be noted that gye’s experi- ments, with a single exception, are concerned with sarcomata. the great merit of his work lies in the experimental evidence it affords of the interaction between an extrinsic and an intrinsic factor in tumour formation and the definiteness it aims at giving, at all events in certain instances, to the characters of the ex- trinsic factor. concluding remarks.—most of the work on biochemical lines is unsuited for remark here, and of the remainder much consists of diagnostic tests for cancer that have been put forward. un- fortunately none of these has stood the test of time. in view of the general belief that cancer in its earliest stages can often be successfully treated by surgery and of the frequency with which the disease first comes under observation at a stage when opera- tion is impossible, a reliable diagnostic method is urgently needed. x-ray examination has facilitated diagnosis of internal cancer particularly when affecting the alimentary tract, but search must still continue for some chemical test applicable at an early date in the disease. brief reference must be made to dawson’s recent work on the melanomata; from a consideration of all the data, and especially the pigment-forming function of epithelial cells, he concluded that the melanomata, usu- ally termed melanotic sarcomata, are epithelial and therefore carcinomatous. action of radium.—in treatment, research has been directed chiefly toward the action of radium and x-rays. at first em- ployed empirically the scientific basis of their action is being discovered by degrees. the x-ray spectrum has been mapped out, and by means of apparatus of very high voltage (180-200 kv.) rays of wave-length and penetrating power approximating to the very short waves of gamma radiation have been produced. 515 the biological action of rays of different wave-length has been studied and radiological treatment is becoming more scientific. there are still wide gaps in knowledge both on the physical and the biological sides and though immediate results can be foretold with some degree of accuracy in certain varieties of cancer, late results often appear to be fortuitous. upon the whole, however, treatment of cancer by radiation is a method with which the clinician has to reckon. this is more than can be said concerning medicinal or dietetic methods, none of which has been supported so far by evidence that can be regarded as sufficient to warrant its serious consideration. (w. 5s. l.-b.) bibliography.—reports and journals: ttfealth organisation, league of nations (cancer sub-committee, at intervals, statistical) ; ministry of health (great britain, at intervals, statistical); medical research council (great britain, at intervals, experimental); the cancer review (british empire cancer campaign, monthly abstracts and reviews); scientific rep, imperial cancer research fund (l.ondon, at intervals, experimental); cancer rep. afiddlesex hospital (london, annual, mainly experimental, 1900-14); journal of cancer research (u.s.a. quarterly, experimental); rep. grafwick cancer foundation (boston, u.s.a. annual, clinical); bull. de passoc. frang. pour v einde du cancer (france, bi-monthly, general); jour. de radiologie (i'rance, bi-monthly, radiological); le cancer (belgium, bi-monthly, radium therapy, general). ; zeitschr. f. krebsforschung (germany, bi-monthly, general); strahlentherapie (germany, bi-monthly, radiotherapy); jamort (italy, at intervals, general); gann (japan, at intervals, general); rep. radium institute, london (annual, statistical); rep. radium institute, manchester (annual, statistical); rep. radin lemmet, stockholm (annual, statistical); rep. radium institute, paris (an- nual, general). 4 textbooks: sir john bland sutton, tumours: innocent and ma- lignant, great britain; e. if. kettle, tumours, great britain, pathological; w. seaman bainbridge, cancer, u.s.a. general, max borst, lehre von d,. geschwiilsten, germany, pathological (1902); h. j. paterson, lectures, post-graduate lectures, 1925, vol. 2. selected original researches: f. 1), bullock and m. r. curtis,‘ exp. sarc. in rats,”’ jour. canc. res., vol. 8, no. 4 (1924); a. carrel and collaborators, ‘‘ tissue culture," jour, exp. azed., numerous papers; j. w. dawson, ‘‘ melanomata,” edinburgh med. jour. (oct. 1925); j. fibiger, ‘ exp. care. in rats by cockroaches,” jour. canc. res., vol. 4, p- 367 (1919); w. e. gye and j. e. barnard, ‘‘ filter passers in cancer,” lancet (july 18 1925); s. kellock, h. chambers and t. h. russ, “immunisation in man,’’ lancet, i, p. 217 (1922); w. s. lazarus-barlow, “ radium in cancer tissue,” brif. afed. jour. (may 9 1914); proc, roy. soc, med., sect. of path., vol. ii (1918) and vol. 15 (1922); w. s. lazarus-barlow and r. h. parry,‘‘ experiments on immunity,” brit, jour. exp. path., vol. 4, pp. 80 and 247 (1923) and vol. 5, p. 34 (1924); w. s. lazarus-barlow and j. i. lecming, “natural duration of cancer,” brit, afed. jour. (aug. 16 1924); a. leitch, “‘ exp. production of cancer,” brit. afed. jour, (sept. 13 1924); t, lumsden, ‘‘ antisera in treatment,” lancet (sept. 12 1925); rivers and pearce, “ filterable virus and sarcoma in syphi- lised rabbits," jour. exp. med. (oct. 1925); peyton rous and colla- borators, ‘' chicken sarcomata,” jour, med., 1911, 13.397, jour. amer, med. assn,, 1912, 59.1793, jour. exp. med., 1914, 19.52; studies rockefeller inst. for med, res., 1913, 16.253.; erwin f, smith, ‘cancer-like growths in plants,” jour. canc. res., vol. i, p. 131 (1916); maud slye, ‘‘ studies on heredity in cancer,”’ jour. cane. res., and elsewhcre numerous papers; k. yamagiwaand k. ichikawa, “tar cancer in rabbits,”’ gann, 1917, 11.19; a. scott, ‘ paraffin dermatoses,” eighth sct. rep. imp. cane. res, fund (1923). caneva, carlo (1845-1922), italian soldier, was born at tarcento (friuli) april 22 1845, and entered the italian army in 1866. he served in the african campaign of 1897, and in 1902 was promoted lieutenant-general. caneva commanded one side in the much-discussed manoeuvres of 1911, his opponent being cadorna and it was probably owing to the result of the manoeu- vres, in which caneva was declared victor, that he was sclected to command the tripoli expeditionary force in oct. rorr. caneva was given a thankless task, being sent to occupy the coast towns in the belief that the turkish garrison, unsupported by the tribesmen, could be easily overcome. he was speedily un- deceived, and for a time could do nothing, as he had no transport and was hampered by orders from home. in spite of these handi- caps he was gencrally considered to have carried the waiting policy too far. he was recalled in sept. 1912, and retired short- ly afterwards. he presided over the commission that was appointed to enquire into the caporetto disaster of 1917. he died sept. 25 1922. cannes, conference of (jan. 6-13 1922), a meeting of the supreme council of the alhes with the primary object of 516 considering the anglo-french suggestions regarding reparations, which had been drafted at the preliminary conference of london on dec. 18-22 1921 (see london, conference of). at cannes, however, the reparation question entered on a new phase through being brought into connection with a project for the general re- construction of europe, and with another project for an anglo- french pact. in regard to reparations the conference opened with a criticism of the anglo-french suggestions by the french minister of finance, who was supported by the belgian repre- sentative. after long and complicated discussions this resulted in a modification of the london suggestions, but a deadlock was avoided, and representatives of germany, as well as the repara- tion commission, were summoned to cannes to make proposals on the basis of the agreement finally reached as between the allies. the wider questions of security and reconstruction were broached by mr. lloyd george in a memorandum submitted to m. briand on jan. 4, before the formal opening of the con- ference. mr. lloyd george’s thesis was that the three problems of reparation, security and reconstruction were inter-related, and that any general scheme for european reconstruction must in- clude russia. in the same document he offered to conclude an agreement by which great britain would pledge herself to assist france with all her forces in the event of unprovoked german aggression upon i'rench soil. in effect this was an offer to revive the anglo-french guarantee treaty which had been signed simultaneously with the versailles treaty (see versailles, treaty of) but had not come into force because that had been conditional upon the ratification of the parallel treaty between france and the united states. at the same time mr. lloyd george warned m. briand at the outset that the british em- pire would not be willing to incur military commitments in central and eastern europe. on jan. 6 mr. lloyd george introduced in the conference a resolution for the convening of a general reconstruction confer- ence to which both soviet russia and the united states were to be invited, and this resolution was adopted by the supreme council, together with an outline agenda. mcanwhile m. briand had been making counter-proposals in regard to the anglo- french pact. the guarantee, he declared, must be reciprocal, and it must be supplemented by a technical military convention. while this second condition would probably have proved an in- superable obstacle from the british point of view, m. briand was violently attacked in the french senate and chamber, in the belicf that he was giving way unduly to mr. lloyd george. on jan. 11 he was recalled to paris by the president of the republic, m. millerand, on the 12th he resigned and therewith the work of the cannes conference was brought to a sudden stoppage. its main results were the provision for the genoa conference and the avoidance of a deadlock over reparations. see british white paper, resolutions adopted by the supreme council at cannes, jan. 1922, as the busis of the genoa conference (cmd. 1621 of 1922); a. j. toynbee, survey of international ajfatrs, 1920-3 (1925). cas, je a)