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Ferentiation

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FERENTIATION).

Experiments in Aetiology.

The frequency with which can cer of the tongue is associated with a jagged tooth or an ill-fitting denture, cancer of the lip with smoking of clay pipes, the occur rence of cancer of the skin in workers with paraffin and tar, of soot cancer in chimney-sweeps, 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 infected 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 a few cases of cancer of the skin have resulted from prolonged exposure to the gamma rays of radium. 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 indistinguishable from cancer by introducing into the gall bladder human gallstones into which small quantities of radium had been introduced artificially. The exact relation of chronic irritation to subsequent cancer is unknown, and there is no doubt that in an even larger number of cases chronic irritation occurs without any subsequent develop ment of cancer. In most instances the chronic irritation must persist over a number of years and the actual cancerous condi tion is preceded by the formation of warty outgrowths and other local manifestations of cell destruction accompanied by cell proliferation.

Tar Cancer.

In the case of tar a cancerous condition of the skin 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 paraffin oils but without success. On the other hand "tars" prepared from isoprene and acetylene by distilling at temperatures between 700 and goo° C. were some of the most effective cancer producers yet known.

Artificial 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 feeding 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 the widely diverse conditions antecedent to can cer, attention was directed towards observations made by Peyton Rous on a chicken sarcoma that could be transmitted by inocu lating 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 instances the special characters of the original growth were repeated 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 to 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 malignant 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 ‘ irus 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.

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 experi mental conditions the virus alone is ineffective; a second specific factor obtained from tumour extracts ruptures the cell defences and enables the virus to infect. Under natural conditions con tinued irritation of tissues sets up a state under which infection can occur. The filtered material isolated by Gye and supposed to contain a virus, after subculture, was examined photographi cally 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 importance but caution must be exercised in its interpretation. Indeed, it still awaits confirmation in some essential points. Moreover, the occurrence of unsuspected minute bodies in what are regarded as nog mal 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 eliminated before Gye's observations can be taken to prove that his filterable virus came from the sarcoma as distinguished from the chicken. Moreover, Rivers and Pearce also found that rabbits bearing intratesticular growths of a trans plantable 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 peculiar to new growths exists but also requires the presence of a specific 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 character izes 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 inflammatory conditions— causation by a particular filterable virus is more easily acceptable and it will be noted that Gye's experiments, with a single excep tion, are concerned with sarcomata. The great merit of his work lies in the experimental evidence it offers as to 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 extrinsic factor.

Concluding Remarks.—Most of the work on biochemical lines is unsuited for remark here; Warburg of Berlin finds that tumour tissue splits up carbohydrates differently from normal tissue and has built thereon a hypothesis for the origin of tumours. Of the remainder much consists of diagnostic tests for cancer that have been put forward. Unfortunately none of these is sufficiently consistent in its results to carry conviction in a particular case. 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 operation 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, usually 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 employed 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 (18o–zoo kv.) rays of wave-length and penetrating power approximating to the very short waves of gamma radiation have been produced. The bio logical 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 f ore told with some degree of accuracy in certain varieties of cancer, late results often appear to be fortuitous. Upon the whole, how ever, 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. Here exception must be made for the lead treatment introduced by Blair Bell which is undergoing vigorous examination in many centres.

cancer, virus, filterable, tumour, factor, rabbits and specific