William F. Koch, Ph. D., M. D.

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WM.F. KOCH, Ph .D., M.D.

THOUGH we fully appreciate the contributions to the study of cancer by both pathologist and clinician, we might expect an investigation of the problem from the viewpoint of the physiologist to reveal something about the purpose and value of this deviation from the normal that is so commonly rated as turmoil and disorder.

The histological expressions of cancer impress us as a desperate attempt at gland production, characterized by its persistence, as a response to a persistent stimulus, by its equalization of cells in proportion to their malignancy, as indicating a singleness in the response type. While the loss of differential structure, and individualization of cells indicates a return to a simple balanced equipment in preparation for a new differentiation along lines so far not developed in the organism. Thus we may infer that the cells are responding to a new or not normal stimulus. Moreover, as the response persistently increases it cannot be adequate, and as structural differentiation has not been accomplished, the effort toward response appears to be only in the earliest stages of development.

Still the cancer process bears strong resemblance to the behavior of several glands of internal secretion that are now established as indispensable factors in the animal economy.

In such simple glands as the parathyroid, we observe acini production by vacuolization and death in cells located farthest from the blood supply. This process is very perfectly imitated in the cancer behavior. Yet in a higher type of gland, as the thyroid, acini production occurs by death of cells close to the blood supply. Thus as cell death is an important phase in the production of the internal secretion of the thyroid, its survival as a method of choice illustrates the adaptation of processes acquired from states of disadvantage in the established service of the organism. Thus we may conclude that the process as occurring in cancer, predicts its future place among the glands of internal secretion. And as limitation and control of activity in an established gland indicates its adequacy, so we must again qualify the cancer effort as at present inadequate in its attempted service. We may therefore infer from the histologic manifestations that cancer has a function in the process of development.

Our chemical studies corroborate this surmise and indicate also the place and value of this function. Our earliest work on the chemical significance of glands of internal secretion was directed toward the explanation of the parathyroid activity. Parathyroidectomy was long known to be followed by a set of tetany symptoms that could be ameliorated by calcium therapy. So the parathyroid glands were universally credited with a vital place in the calcium metabolism. This supposition fell short of agreement with so many experimental facts that the theory could not be sustained. Should a farmer or even a pharmacist observe an animal in the tetany of parathyroidectomy, he would certainly say the animal was poisoned. And after a careful checkup of the calcium theory we choose to direct our research along the “farmer” hypothesis.

After developing a suitable method of isolation, we were able to isolate uniformly from the urine of parathyroidectomized dogs, toxic quantities of guanidine bases. The concentrations of these poisons were proportionate with the rapidity of development and severity of the symptoms and the earliness of fatality. We proved them the responsible factors for the symptoms and death of the animals. Thus it appeared that the parathyroid protected from a toxic agent. Our work was amply verified by Paton at the University of Glasgow whereby he earned the Triennial Prize in medicine awarded by Harvard University.

Yet the guanidine bases were only incidental to the loss of parathyroid activity as we later proved by the isolation of the guanidine precursors the cyanamides, very simple fundamental metabolic inter-products. These cyanamides easily took up an ammonia radical to become the guanidines in which form they were excreted. The cyanamides are evidently products of activity of other factors than the parathyroid and were not metabolized further after parathyroid removal. So we assume that the parathyroid disposed of the cyanamides in their activity for further benefit to the organism as a whole. We cannot go further into this subject here but cannot omit it as it exemplifies an established gland activity serving as a protection of the organism against a definite toxin. Likewise we shall find evidence that the cancer behavior is a protective response to a toxic product generated within the body. The localization of the cancer effort in congested areas indicates that the exciting stimulus is distributed through the blood stream.

Clinical observation discloses the persistence of toxemia over a period even as long as twenty years previous to the advent of the growth. After the growth has come these toxic manifestations disappear completely or nearly so. After a surgical removal of the pre-growth they return, and with recurrence of the growth again disappear. We designate these symptoms as the pre-growth symptoms, for they differ from those consequent to the activity of the growth itself.

The pre-growth symptoms caused by the toxin-stimulus are mainly manifestations of interference with normal nerve function, and predominately with certain mechanisms of the central nervous system. Thus in a series of two hundred cases distinct mental aberration, incorrectly diagnosed as paranoia, was observed in two percent of cases. But the prevailing disturbance is an interference with function of the second and third nerve mechanism. Thus an optic-migraine without much or any headache or aural disturbance, or an optic-vertigo with scotomata, might express the condition. I have not been able to find a discussion of this complex in the literature and propose to take it up in a further paper. However, I may indicate the main characteristics, as they occur in fully eighty per cent of my cases.

The points of disturbance lay both in the perception centers for optic impulses and those centers where optic impulses arc conveyed into paths of motor control, of both the optic apparatus and the general musculature.

Thus visual impulses, in one case, periodically caused muscle tremors arid convulsions. Covering the eyes gave relief. In several cases teichopsia gave the impression that the patient persistently saw needles and pins wherever she looked, and she was diagnosticated to be a paranoiac. Difficulty in accommodation results in a large proportion of cases in a haziness of all objects closer than or beyond a distance of usually some ten feet from the patient in these cases attempts at accommodation give rise to a sensation of sickness but not nausea particularly. Temporary blindness of the whole or part of the visual field is common, so that a patient may run into things without seeing them. Or a sudden general loss of sensation with blindness and a complete loss of muscle control, causing the patient to drop to the ground, without loss of consciousness, giving the impression of dying. The muscle control may be only partly lost and movements consequently be in coordinate. During these spells pinpoint pupils have been reported. Great changes in visual impulses, as occurring on turning out the light or waking up in the morning, may cause dizziness with topsy-turviness of after-images or true images. In the former case turning on the light and fixing the eyes on an object relieves. In the latter case closing the eyes relieves. These occurrences come in spells of only short duration or lasting several weeks at a stretch and over a period of a few or as long as twenty years prior to the development of the growth.

Occasionally a peripheral neuritis is present. It may be mild or severe and may be associated with areas of anesthesia and paralysis of one or more groups of muscles. But the percentage of such cases is small.

Since these symptoms, which occur in nearly ninety percent of my cases, let up entirely or in large part with development of the growth, its detoxicating function is evident, and resembles the detoxicating function of the parathyroid, which removes the cyanamides from the blood.

The cancer cells absorb and hold the stimulus-toxin in combination without changing its chemical identity for the most part. That is, they store it. This is proven by the fact that with dissolution of the growth following our treatment, the stored toxin is again liberated with return of the pre-growth symptoms, until the growth has entirely been digested and eliminated.

The cancer cells, also in small part and continually, alter the stimulus-toxin, but instead of changing it to a harmless or useful immune body, as the parathyroid are able to convert the cyanamides, these cancer cells only produce an even more harmful poison. Thus the cancer products cause loss of weight and strength and a progressive anemia—the symptoms of the growth period. That this is the result of cancer-cell activity is proven by the quick cessation of these symptoms very shortly after our treatment is given. For within a week usually a gain in weight and blood count ensues, even before noticeable change in the dimensions of the growths take place. Moreover this cessation of activity is coincident with the uniform coagulation and calcification of every cancer cell in the body. And we recognize calcification to be the first stage in digestion of the body proteins. Thus the secreting activity of the cancer cells is cut short by the institution of their digestion shortly following treatment.

The type of disposal of the involuting cancer material also bears strongly on the interpretation of its function. For its digestion is the same as takes place in the development of bone or the organization of a blood clot, or even the digestion of milk. Here the first step is the production of a calcium-proteinate from which the protein can never again be reclaimed undenaturized. Thus to all intents and purposes the calcified cancer tissue is dead and prepared for removal, as occurs in the organization of a blood clot or the clearing out of the inside of the developing bone. Our slides of specimens removed at various periods following treatment show that calcification is uniformly established within two weeks and that the other steps that complete the removal process are associated with the in-growth of angioblastic tissue, as occurs in developing bone and the removal of a blood clot. This process continues until all traces of the cancer tissue are cleaned out. Angioblastic tissue replaces the cancer tissue and contracts down, and, undergoing autolysis, finally also disappears, only leaving a scar where mending of a destroyed wall is necessary.

The material absorbed from the involuting cancer is used in replenishing the exhausted tissues of the patient. This is exemplified in patients who, though unable to move their legs in bed from weakness, within ten days after treatment had gained sufficient strength to support their bodies, though not having been able to take food. Thus the method of removal and disposal of the involuting cancer tissue is exactly that used in serving other physiological processes.

The strongest and the sufficient proof that cancer is a response at protection against a definite toxin, however, rests with the fact that removal of the toxin from the body and destruction of the toxin’s source is followed by complete involution of all cancer tissue, complete healing of the regions involved, return to health with absence of growth and pre-growth symptoms, and the absence of recurrence. (Cases cured in 1918, still remain cured.) The cancer tissue then becomes obsolete and disappears when the function it attempts is performed for it.

The histologic, physiologic, and clinical relations in the development, behavior, and involution of cancer therefore, identify it with a physiological effort and a protective function, or immunizing attempt, which though inadequate at present, promises at some future time to be instituted in the animal economy as a definite function, perhaps as a gland of internal secretion like the parathyroid, and able to overcome one more opposing force in our environment. Cancer then represents an attempt at specialization of function in which all tissues now compete.

The chemistry and source of the toxin, the synthesis of a successful anti-toxin, and the mechanism of immunity (a provision for conversion of a toxin into such chemical modification that it is harmless to the host, and destructive to its own source, the infecting agent), as exemplified in our work will be detailed in a further report.

KOCH: Jour. Biol., Chem., 1912, XII, 313.
KOCH: Jour. Biol. Chem., 1913, XV, 43-6.
PATON: Quart. Jour. Phys., 1917, X, No. 3 and 4.
KOCH: Jour. Lab. and Clin. Med., 1916, i, 299.
KOCH: Jour. Med. and Surg., Jan., 1918, 1-9.