Columbia ®mber2iitp\ intJjeCitpofJgeia^gork COLLEGE OF PHYSICIANS AND SURGEONS Reference Library Given by Digitized by tine Internet Arciiive in 2010 witii funding from Open Knowledge Commons http://www.archive.org/details/canceritsnaturecOOgree /^^-p^-t// ^ V^ix^euj 6-< ^^^e-f P *2^ t //-/ CANCER ITS NATURE, CAUSES, DIAGNOSIS AND TREATMENT ROBERT HOLMES GREENE, A.M., M.D., F.A.C.S. EMERITUS PROFESSOR OP SURGERY, MEDICAL DEPARTMENT OP FORDHAM UNIVERSITY, ETC. PUBLISHED BY JAMES T. DOUGHERTY 409 West 59th Street New York City 1918 COPTEIGHT, 1918 BT ROBERT HOLMES GREENE PREFACE The views expressed in this volume are the results of the labors of a surgeon and a physiological chemist, working together for the past few years. The chemical work has been done by John A. Killian, Ph.D., Patho- logical Chemist at the House of Calvary for Cancer, and formerly Instructor in Physio- logical Chemistry at Fordham University. No attempt has been made to settle definitely many of the questions arising in connection with this wide-spreading disease, but an effort has been made to show the lines along which future investigators probably must work. In addition, the result of the labors of the au- thors is presented, both as to methods of diagnosis which they have found useful, and as to principles and details of treatment, the carrying out of which may ameliorate some of the suffering and at least often retard fur- ther progress for a considerable length of time. We wish to thank the following individu- als for valuable aid rendered us in the prep- PREFACE aration of this volume, for suggestions, aid given in obtaining manuscripts, as well as for the carrying on of investigations^ which have both directly and indirectly resulted in this production: Drs. E. W. Caldwell, H. H. Janeway, J. H. Larkin, L. Fetzer, Ph.D., Max Kahn, Douglas Quick, and R. J. E. Scott; also Mr. J. S. Brownne, N. Y. Acad- emy of Medicine; Rev. Walter Dwight, S. J., Rev. John J. Wynn, S. J., Mrs. Marie Killian, Mr. Louis Pine, Mr. Louis Protz- mann, Mrs. L. Smith, and Mr. E. C. Stein- ach, Ph.G. Robert Holmes Greene, 78 East 56th Street, New York City. June I, 1918. CONTENTS Part I. CAUSES OF CANCER CHAPTER PAGE I. Etiology of Cancer 9 II. Heredity 23 Part II. NATURE OF CANCER I. Nature of Cancer 30 II. Precancerous Conditions 54 Part III. DIAGNOSIS OF CANCER I. Details of Methods of Sulphur Findings in the Blood and Urine 60 II. Diagnosis by Chemical and Bacteriological Means 72 III. Diagnosis of Malignancies of the Stomach. . 81 IV. Differential Diagnosis between Epithelioma, Syphilis, and Diseases of the Skin 90 V. Diagnosis by X-Ray and Cystoscope 95 VI. General Consideration of the Condition of the Blood, Hair, Nails and Saliva 107 Part IV. TREATMENT OF CANCER I. Basis of all Successful Treatment to be Found in Measures Which Tend to Increase Tissue Metamorphosis 112 II. Vanadium and Arsenic. Iron and Mangan- ese. Condurango, and Other Bitter Tonics 121 III. Radium, and X-Ray 132 IV. Excision 139 V. Selenium and Tellurium 144 VI. Preparations for Cleansing, Deodorizing, and Disinfecting Cancerous Lesions of the Skin 157 VII. General Considerations 168 PART I CAUSES OF CANCER CHAPTER I Etiology of Cancer In the whole field of pathology there is no problem at once more essential and more baffling than the disclosure of the causes in- citing and promoting the growth of tumors of all kinds. The question of the origin of the unchecked proliferation of cells and the transmission of the resulting neoplasms to foreign hosts has occupied the minds of ex- perimentalists and clinicians as well for cen- turies, and although a number of ephemeral theories have been proposed, at the present day we are as ignorant of the etiology of can- cer as we were when the study first began. It is to be lamented that many investigators, far from adding to our knowledge upon this subject, rather have introduced confusion by the invention of new nomenclatures and 9 lO CANCER the adoption of complicated classifications. However, it is not our purpose to enter into a lengthy philosophical discussion or specu- lation upon fantastic theories of tumor etiol- ogy, but rather as a working basis for the clinicians to point out the salient features in our conception of the cancer process and to emphasize those factors which we believe predispose to malignant tumor formation. In the production of a malignant neoplasm there is a combination of factors of two kinds, the predisposing or intrinsic factors and the exciting or extrinsic factors. Concerning the nature of these intrinsic causes we have at most only hypotheses to offer. No individual theory, not even a combination of them all, ofifers an adequate explanation; but inasmuch as each contains some truth of value to the clinicians, they merit serious consideration. Intrinsic Causes Cohnheim's Theory According to Cohnheim, the malignant neoplasm has its inception in groups of cells that have become arrested in the development of the foetus. These cells maintain an em- bryonic character and do not enter into the ETIOLOGY 1 1 composition or the functions of adult tissues. They are therefore called embryonic ''rests." Malformations in the development of the hu- man body are of frequent occurrence, e. g.y moles, clefts, naevi, etc.; and it has been the experience of every observer that these de- fects are more frequently the sites of malig- nancy in later years than the normal adult tissues. It seems logical to assume, therefore, as Cohnheim does, that there may exist congen- ital, microscopical defects in the formation of tissues, /. ^., certain groups of cells become arrested and isolated in development, form- ing "rests." Every mature cell has a twofold purpose, (a) growth, (b) the performance of some specific form of work, e. ^., secre- tion, contraction, etc. Since the cell rests do not mature, they have but one form of activ- ity — growth. These cells may remain quies- cent in the tissues of which they were in- tended to become a part, or they may be transported to other portions of the body. Throughout this period of quiescence the cells maintain their vitality undiminished, but upon the intervention of an exciting cause, e. g., irritation, inflammation, etc., they are incited to an unrestricted proliferation pro- 12 CANCER ducing a malignant tumor. It is difficult to understand why the tumor lies latent for so many years. The most probable explanation is the following: During health the activity of the neighboring cells of the tissue or organ hold the embryonic "rests" in abeyance; but when the functions of the tissue or organ be- come hampered by injury, inflammation or senility, the normal cells enter upon a retro- gressive process, and the dormant "rests," no longer constrained, but still possessing their embryonic vigor, begin a process of growth, paralleled only by that of the embryo. Every clinician will find many of his ob- servations in accordance with this theory. It is most frequently after the menopause that carcinomata develop in the uterus and breasts, and in a large majority of cases of malignancy of the stomach a previous history of gastric ulcer of alcoholism can be obtained. There are, on the other hand, many weak points in Cohnheim's hypothesis. It neces- sarily must assume a widespread distribution of cell "rests" if a group of cells is to be present wherever a form of irritation may be encountered. Moreover, this theory alone fails to account for the essential characteris- tics of a malignant neoplasm — its atypical ETIOLOGY 13 growth and the formation of metastases. Al- though many tumors are fcEtal in character in the human body, the existence of dormant embryonic cells has never been demonstrated. Ribbert's Theory In common with Cohnheim's hypothesis, Ribbert ascribes the origin of a malignant tumor primarily to an isolated group of cells. However, according to the latter authority, the process of isolation is attributed not to any defect in the development of the cells themselves, but rather to an atypical develop- ment of the subjacent connective tissue. The initial stimulus, then, to tumor formation is an hyperplasia of the connective tissue, in- duced by trauma, irritation or chronic inflam- mation, which severs the original physiolog- ical connection of a group of epithelial cells from their neighbors in the same tissue or organ. Thus isolated, these cells are no longer subservient to the common cause of the tissue or organ, but they are still imbued with an embryonic capacity for growth, and if the check upon growth is removed by diminished resistance, they proliferate at will, thus pro- ducing a malignant neoplasm. 14 CANCER Of interest to the practitioner are these points in Ribbert's hypothesis: (a) The process of "rest" isolation may be post natal as well as foetal, e. g., in the heal- ing of a wound or in the disturbance of physiological connection of a portion of a tissue or organ in a surgical procedure. (b) There exists a precancerous stage: e, g.j a chronic dermatitis may be a precan- cerous stage in the formation of an epitheli- oma. Or in the development of carcinoma of the tongue there will be a pre-existing sub- epithelial reaction. (c) Tumors are unicentric. They pro- gress by the division of their own cells, and there is no transitional zone between the tu- mor itself and the normal tissue. It may invade and thrust apart the surrounding cells, but it does not convert them into tumor cells. Ribbert's theory, however, does not coin- cide with facts of common knowledge. Ac- cording to this hypothesis a condition most favorable to the production of a tumor would be the healing of a wound; but a malignancy in this condition is very rare. Moreover, in skin grafts a proliferation of tissue has never been recorded. ETIOLOGY 15 The Parasitic Theory In a certain biological sense every neo- plasm is a parasite, for it lives and grows at the expense of another organism — its host. It is not, however, with this significance that we speak of the parasitic nature of cancer. The earliest observers ascribed the origin and the propagation of the disease to microorganisms, and even at the present day a few authorities adhere to that view of cancer formation. The theory of the parasitic origin of ma- lignant tumors is not without some founda- tion. Although it is not uncommon to find bacteria in and around malignant growths, there is no evidence to connect their activity with tumor formation. We must always bear in mind the fact that the ulceration is not the cancer^ but that in the vicinity of a malig- nant neoplasm the natural protective powers of the tissue cells are inhibited, and therefore the site of a malignancy becomes a fertile field for bacterial growth. One of the authors has had the opportu- nity of following several cases of cancer that received B. Prodigiosus vaccine. One of these cases, in which the site of operation did not heal following the removal of a tumor 1 6 CANCER from the abdomen, manifested no improve- ment. In the other cases of epithelioma with superimposed suppurative processes, an ap- parent improvement in checking the progress of the infection was observed. This improve- ment must be attributed to a stimulation of antibody formation in the blood of the host which enabled the host to ward ofif the infec- tion, but not the neoplasm. All the cases, however, terminated fatally. Minute bodies, of an intracellular or an extracellular type, with staining properties essentially different from the tumor cells, have been demonstrated about cancerous growths. Some authorities, as Russel and Romcalli, have considered them blastomy- cetes, while others look upon them as intra- cellular protozoa. It has been found, how- ever, that their occurrence is not confined to malignant neoplasms, but they also frequently accompany inflammatory conditions. It is generally agreed now that these bodies are products of the cell metabolism suspended in the cytoplasm or extruded into the intracellu- lar spaces. The all-important and much mooted ques- tion of the infectivity of carcinoma and sar- coma depends upon the substantiation of their ETIOLOGY 17 parasitic origin. That there is a strong popu- lar conviction of the possible transference of the disease from one person to another is evi- dent to everyone experienced in history-taking among patients of this type. The onset of the malady will be dated from and attributed to actual contact with an affected person, as in the dressing of a cancerous patient, or the use of the same dishes or drinking cups. If carefully examined, it will be found that with the exception of a few striking coincidences, the greater part of these histories will not bear scrutiny. On the contrary, we possess the more reliable evidence that there is no instance on record of an infection among nurses, clinicians or pathologists, nor do they possess an undue liability or immunity toward cancer. The only evidence conclusive of the existence of a parasitic micro-organism as the causative agent in the production of can- cer would be the actual demonstration of the microbe invariably present in tumors and capable of producing histologically identical growths when transmitted to other hosts. The lack of such evidence, however, leaves the question an open one. It is indeed true that all types of micro-organisms, cocci, bacilli, blastomycetes, protozoa and metazoa, have at 1 8 CANCER one time or another been associated with the etiology of cancer, and in fact the variety of these alleged causative agents, far from con- vincing, has rather increased our scepticism. For a time the Micrococcus neoformans^ de- scribed by Doyen, received more serious con- sideration than the others. The Micrococcus neoformans is closely allied to the Staphylo- coccus albusj and, according to Doyen, is in- variably found in the vicinity of new growths, and animals experimentally inoculated with the coccus develop malignant neoplasms. Later workers, however, have not only failed to isolate the organism from malignant tu- mors, but they have shown that many tumors are sterile. There can be no question but that certain parasites, such as metazoa, play an important role in cancer formation, but their causation is rather secondary than primary, /. ^., one of irritation. We can conceive of a chronic irri- tation due to a parasitic infection, stimulat- ing a latent malignancy in an organism where the primary cause, /. ^., predisposition, was previously active. But the influence of the parasite in such a case is in no way analogous to the part taken by the tubercle bacillus in the production of tuberculosis. ETIOLOGY 19 The results obtained in the experimental production of cancerous growths have demon- strated beyond a possibility of doubt that for the successful transference of a neoplasm from one host to another the intact cancer cell is essential. Attempts to inoculate animals with products of the cancer cells, or with para- sites isolated from the growth, have invari- ably failed. If, therefore, a specific organism does exist, it must be essentially different from all micro-organisms within the scope of our present knowledge. In view of the evidence afforded by clinical observations and experimental study, we must not regard can- cer as a parasitic disease in the accepted sig- nificance of that term. There is then no possibility of infection save by inoculation with the living cancer cell. Further, although the ulceration is not the cancer or the cause of it, there is every need of keeping the growth aseptic by agents described in a later chapter, if we are to preserve the vitality of the neighboring tissue cells and to assist their protective forces. The theories so far discussed are not indi- vidually sufficient to account either for the formation, propagation, or the transmission of malignant growths. All of them have 20 CANCER many good points; so, too, all of them have their weak points. It will be noted that they bring into consideration the pathology of ma- lignant tumors. In fact this might be ex- pected when we recall that their authors were pathologists of the old school, who considered nothing worthy of consideration unless it could be shown under the microscope. How- ever, with the recent advance in the chemistry of living organisms, many facts have been brought to light that have revolutionized our conception of the factors influencing the de- velopment of pathological conditions. Re- cent investigations in the composition of the blood and the other body fluids, in patients suffering from carcinoma and sarcoma, have demonstrated that these fluids differ widely from the composition of normal fluids. It will be observed, as stated in a later chapter, that the blood of patients suffering from malig- nancies shows an increase in non-protein nitro- gen, as well as an increase in non-protein sul- phur. Our own investigations have shown that this increase in the non-protein and non-oxi- dized sulphur, continually known as neutral sulphur, shows also in the urine. It is also men- tioned by Greenwald, "Increase in sulphur in Urine," Journal of Cancer Research^ ^9^7- ETIOLOGY 21 There are two possible exceptions to the occurrence of the abnormal amount of nitro- gen and sulphur in the blood. They may be due to the presence of a combination which we call toxemia, being both nitrogen and sulphur, but differ from the ordinary com- pounds with which we are familiar in the blood, as urea and so on. The presence of this toxemia may incite epithelial cells or con- nective tissue cells to an unrestricted prolif- eration. It may be that these cells are iso- lated from their neighbors, as rests, as Cohn- heim thinks, but the exciting cause would be the presence of this compound or compounds detected by the increase of nitrogen and sul- phur in the blood stream. It is interesting to note in this communication that Jacques Loeb has recently shown that unfertilized ova may be incited to greater and more mature devel- opment by the agency of certain chemical substitutes. In an analogous manner the presence of this compound or compounds in the blood stream may incite cells to unre- stricted proliferation. On the other hand, the compound containing this nitrogen and sulphur may be a product of the metabolism of the carcinoma or the sarcoma, which finds its way into the blood stream. If this latter 22 CANCER view be true, then the metabolism of the ma- lignant cells varies from the metabolism of healthy cells, because in the latter case we find as metabolic products, urea, creatinine, and uric acid. The compound indication of the presence of the malignancy is none of these three. No matter what our conception of the nature of a cancer may be, the fact re- mains that its presence in the organism is attended by an increase of the non-protein nitrogen and sulphur, and this fact is most valuable in diagnosing a latent malignant tumor or in differentiating a malignant from a benign tumor. CHAPTER II Heredity The subject of heredity in connection with malignant growth is such an important one, and one which at the present time is attract- ing so much attention, that we feel obliged to mention it, although our views concerning it are not so well fortified but that they are sub- ject to modification in the future as a result of the publication of investigations that are being carried on at the present time by work- ers in this field. If the human organism reacted to disease in exactly the way that certain animals do, such as mice, we would be justified in hold- ing the same conceptions concerning the na- ture of this disease as are held by Miss Maud Slye, of the Ortho Sprague Institute, Chi- cago, the results of whose researches have been published from time to time in the Journal for Cancer Research during the years of 1916 and 1917. Her results seem to show that mouse cancer is transmissible exactly ac- 23 24 CANCER cording to the laws of the so-called ^'Men- delian Theory." This theory was first pro- mulgated through work on peas by Gregor Johann Mendel in 1866, and within the last ten years has attracted much attention. The most exhaustive of many works on the sub- ject, and one to which we would call atten- tion, is that by Bateson, published in 1913. The theory can be perhaps more easily illus- trated by giving the results of some investi- gations on Andalusian pigeons, results which correspond with the work done by Mendel on peas. If fifty white and fifty black Anda- lusian pigeons are mated, the result would be one hundred blue pigeons. If these blue pigeons, which are the second generation, are mated among themselves, the result in the third generation will be twenty-five white, twenty-five black, and fifty blue pigeons. The twenty-five white would breed true to white, the twenty-five black would breed true to black, and the fifty blue would continue to breed the following generation in the same proportion, one-half blue, one-quarter white, and one-quarter black. Quoting from the Catholic Encyclopedia under ''Mendel," the results of his work on peas were as follows: "In the case of the pea, HEREDITY 25 he observed that some were tall, some dwarf in habit; some had round seeds, others wrin- kled; some had green endosperm, others yel- low. For the purpose of his own observation he selected seven such characters and studied their behavior under hybridization. From what occurred he was led to believe that the progeny of the various crosses behaved in regard to these characters not in a haphazard manner, but in one which was reducible to the terms of a so-called ^'Natural Law." One instance given by Bateson will explain what happens: there are tall and short (or ''Cupid") sweet peas, and in them we have plants showing a pair of marked and easily recognizable opposite characters. The tall and short forms are crossed with one another, and the seeds are collected and sown. The resultant plants will be found to belong en- tirely to the tall variety, which has apparently wiped out the short. If, however, this gen- eration of seeds is sown and the flowers of the resultant plants be self-fertilized, the re- sult is that, when their seeds are sown and have sprung up into plants, it is found that these are mixed, and mixed in definite pro- portions, for on the average it will be found that there are three tall forms for every one 26 CANCER of the short. It follows that the dwarfishness was not wiped out, but that it was tempora- rily obscured in the second generation, though present all the time potentially. To the char- acter which alone appears in the first cross is given the name dominant (in this instance tallness is dominant) and to the hidden char- acter that of recessive (dwarfishness in the example). When the tails and dwarfs of the third generation are allowed to be self-fer- tilized, it is found that all the recessives (dwarfs) breed true, and what is more, will go on breeding true as long as uninterfered with. Not so with the dominants which, after self-fertilization, produce both tails and dwarfs. Some of the tails of this generation will breed true and continue to breed true; others will not, but produce a mixed progeny. Hence, out of the first plants, seventy-five will be tails (dominants) and twenty- five dwarfs (recessives), these last being pure. Of the seventy-five tails, twenty-five will be pure and w^U go on producing tails; fifty will be mixed, and their progeny will consist of pure dominants, mixed dominants, and recessives, as has been stated above." As we have understood the work done by the investigator in mouse cancer, previously HEREDITY 27 referred to, transmission of cancer in mice follows out Mendel's laws along the lines above mentioned. And not only does it seem true about mouse cancer in general, but cer- tain types of cancer in them, like cancer of the liver (by proper mating of the mice), seem to develop according to Mendel's laws. We are inclined to believe that, as regards human beings, statistics so far are unable to demonstrate any such conditions as those in the mice above referred to, but it is one of those matters that time and proper study of cases and their classification will finally clear up. Somewhat generally speaking, there seems to be no doubt that a tendency to cancer ex- 1 ists in some families; and if this be true, as we believe it to be, we may also recall the physiological suggestion referred to in other chapters, that a toxin may pass from the pla- ) centa to the foetal circulation, predisposing the foetus to a malignant formation at the in- tervention of the secondary cause. It appears, to us that, if cancer is inherited, the geo- graphical history of cancer should have some bearing on the subject, and to some extent we have carried on investigations of our own in- 28 CANCER this direction, although not enough to have derived from them alone positive conclusions. Investigations as to the character of disease on an island (Pitcairns Island), which is so remote from civilization that mixture of for- eign blood has practically never been intro- duced, shows that cancer has never been seen. This is on the authority of Miss McCoy, a trained nurse, a resident of the island, who recently visited this country. On some other small islands, not far from each other, in the West Indies, but not so much isolated, there is a large mortality from malignant growth, while in the neighboring island it is very small. The above data, while not conclusive, and not definite enough to be of much scientific value, strengthen our views as to the part played by heredity in cancer. This, combined with what we have been able to find out about the animal transmission as mentioned above, with the knowledge we have of the transmis- sion of other diseases resembling cancer, backed up with our clinical experience — while the exact method, the exact proportion, or the exact laws governing such transmissions in human beings is still a subject to be defi- nitely settled in the future — have given us a HEREDITY 29 very positive belief that there exists a hered- itary tendency to cancer transmission; but with the exact physiological and anatomical laws governing these we are not as yet fa- miliar. PART II NATURE OF CANCER CHAPTER I Nature of Cancer We wish to make it clear that, in this chap- ter as well as the preceding ones, we have no desire to overload this little volume with ma- terial which can easily be obtained by those particularly interested in the subject, more fully from many of the more recent works, written by men more familiar than ourselves with the pathological and histological tech- nique; but it has seemed wise to call atten- tion to the conclusions most generally accepted at the present time, hoping that by such means this book may be more of an aid to those in- terested in the diagnosis of cancer who may not have the opportunity to obtain this infor- mation or are not already conversant with it. At the same time it helps to make clear any theories of our own we have desired to pub- lish and enables us to present the results of 30 NATURE 31 any original work which we have done in a somewhat more suitable setting. Cancerous growths partake of the nature of tumors, and hence a discussion of the characteristics of tumors from a pathological standpoint will be essential before we can consider the minute structure of cancerous growths. Powell White has defined a tumor as a mass of cells, tissues, or organs, resem- bling those normally present in the body, but arranged atypically, which grow at the ex- pense of the organism, without at the same time subserving any useful purpose in the host. This definition most satisfactorily ful- fills all the conditions noted by pathologists or surgeons in connection with tumors in gen- eral. All tumors are derived from pre- existent cells of the body, which they re- semble more or less closely. However, in certain conditions the characteristics of the cells may revert to a primitive form so that they no longer resemble the cells of the tis- sues from which they were derived. Hence their origin is defined. Tumors whose cells preserve the characteristics of the original tissue or organ are called typical growths, but where the original characteristics of the parent tissue or organ are lost the growth is 32 CANCER spoken of as atypical. All tumors are com- posed of two structures, a matrix or stroma, and the parenchyma or the tumor cell proper. It is the nature of the parenchyma that gives the tumor its distinctive features. In various tumors a wide variation in the relation of the parenchyma to the stroma will be noted. The general statement may be made that benign tumors are typical. In malignant tumors, on the other hand, the cells differ considerably from the parent cells. There is noted a re- version to the embryonic or vegetative form of cell, and this reversion is spoken of as ana- plasia. There exists a close relationship be- tween the histological structure of the cell and its pathology. That is to say, in innocent tumors the cells which still preserve the morphology of the parent may continue to perform the functions of the organ or tissue from which they were derived; but, on the contrary, in malignant tumors where a varia- tion from the prototype occurs, all functions are lost except that of growth. In the nucleus of the parenchymatous cells some new changes will be observed in typical growths. The nuclei are normal, but in atypical growths wide variations occur in the size or shape of the nucleus, or in multiplication, or in de- NATURE 33 generative changes. The most common form of variation occurs in the character of cell division; that is, in rapidly growing tumors instead of indirect cell division or mitosis we shall note particularly around the margin of the growth evidences of direct cell division or karyokinesis. The supporting network of the tumor or its matrix is an outgrowth of the stroma from the parent tissue. It carries the vascular and lymph supply to the tumor. In the benign type the blood vessels are well developed, but in the malignant type they are capillaries, and very often consist merely of a lining of endo- thelial cells. The lymph supply is principally through lymph spaces. No nerves have been found in tumor stroma. Occasionally around the periphery one may find nerve tissue that has become incorporated in the tumor by the invasion of neighboring tissue. A sponta- neous disappearance of a tumor or a check in its growth may occur, owing to a prolif- eration of the connective tissue which chokes the neoplastic elements. However, under other conditions the stroma may assume ma- lignant characteristics and proliferate in pro- portion to the parenchyma. Or, on the other hand, it may undergo calcareous degenera- 34 CANCER tion. In innocent tumors no variation in the character of the connective tissue will be found and the parenchyma and stroma occur side by side. The method by which tumors proliferate has been a subject of dispute among patholo- gists. Some authorities have claimed that the tumor cells cause a degeneration in the cells of neighboring tissue, and that this de- generation is a reversion to the type of cell in the parenchyma of the tumor. These de- generative, changes have been reported prin- cipally around the periphery of the tumor, but it has been impossible to substantiate such a claim, because what may appear to be a sin- gle tumor, on careful examination will ap- pear to be a multiple tumor. However, the more logical view entertained by the majority of pathologists is that tumors are unicentric, that is, they propagate by expansion and in- filtration. When a tumor occurs by expan- sion the increase in the tumor substance is uniform throughout. This type of growth is the rule in typical tumors. Malignant tumors prefer to grow by infiltration, that is, by peripheral extension, with little or no growth in the center of the tumor, in fact the central portion, deprived of its blood supply, may NATURE 35 undergo a degenerative change or a necro- biosis. From the point of view ot the sur- geon and the clinician the most pertinent classification of tumors is into groups, the innocent and the malignant. The clinician's conception of malignancy is radically differ- ent from that of the pathologist. To the clini- cian the growth which eventually entails a fatal termination of the host is considered malignant. The pathologist, on the con- trary, classifies as malignant those tumors whose cells possess definite characteristics, and the tumor as a whole manifests properties which experience has shown to necessitate a fatal prognosis to the host. In other words, to the clinician the criterion of malignancy is the prognosis, but to the pathologist it is the properties of the gross structure and its his- tological characteristics. Those properties which have been found by experience to be invariably associated with pathologically ma- lignant tumors are, first, rapidity of growth; second, the vegetative or embryonic nature of the cells; third, infiltration; fourth, the for- mation of metastases leading to a local recur- rence; fifth, ulceration; sixth, a tendency to degenerative changes; and, seventh, the pro- duction of cachexia and subsequent anemia. 36 CANCER The rate of growth is not an invariable in- dication of the nature of the tumor. The general statement that malignant neoplasms manifest a rapidity of growth, while benign tumors are slow growing, admits of many ex- ceptions. A slow-growing tumor is not nec- essarily innocent. Sarcomata, however, are almost invariably rapid in growth. Micro- scopically, this rapidity of growth is indicated by a peripheral invasion of adjacent struc- tures and in the peripheral cells there will be noted numerous points of mitosis. The growth of the malignant tumor is independent of the physical condition of the host. Character of the Cell. — It was noted above that cells of malignant neoplasms manifest a tendency to a reversion to the primitive type, and this reversion has been called by Hause- mann "anaplasia." For mature cells, posses- sion of two functions is necessary: (i) of growth, and (2) the performance of some specific work, e. g.^ secretion, contraction, and so on. When such a cell undergoes a process of anaplasia its specific function is lost, and all the energy within the cell is expended in unrestrained growth. Microscopical exami- nation of cells will show evidence of the per- formance of their specific work, as, for in- NATURE 37 Stance, the cells of mucous membranes will be observed to contain mucin, and this mucin occurs in the cytoplasm, and frequently gives the cell a goblet appearance. When anaplasia takes place, the cytoplasm vs^ill be seen to have diminished. The goblet appearance of the cells is no longer noted and the nuclei are relatively larger than under normal condi- tions. It must be borne in mind, however, that a diagnosis cannot be made upon changes in one cancer cell, but an examination of the tumor as a whole must be made, and if ana- plasia is noted to be the rule throughout the tumor, then it may safely be classified as ma- lignant. Metastasis. — The characteristic of neo- plasms of the malignant type, which renders their removal by surgical means a practical impossibility, is the ability to form secondary growths of a similar character at a distance from the original tumor, and this character- istic is called metastasis. But metastasis must be distinguished carefully from a local re- currence. The latter is the reappearance of the malignant process in the immediate neigh- borhood of the original neoplasm. The for- mation of metastasis has been shown to be due to the spreading of intact cancer cells from 38 CANCER the primary focus to a distant site by a combination of three processes: first, by the lymphatic system; second, by the venous sys- tem; and third, by the arterial system. In a dissemination of cancerous cells the lymphatic system plays the most important part. Such, however, is not true of sarcomata, and most probably this is due to the fact that the char- acteristic cells of sarcoma, which are larger than those of carcinoma, cannot pass through the lymph walls, and consequently they are passed on to the vascular system. The car- cinomata cells, however, filter out through the lymph walls before they reach the vas- cular system. Cells from primary cancerous growths may escape into the lymph system, where they will be transported until they be- come fixed, and at such point of fixation they proliferate and produce a secondary growth. Cancer cells from the primary growth may escape into the lymphatic system. An accu- mulation of such cells and their fixation, with consequent proliferation along the lymphat- ics, may cause the formation of a series of nodules, thus producing what is known as lymphangitis carcinomatosis. On the other hand, the cells may not become fixed until they reach the first lymph glands. The pro- NATURE 39 liferation of the malignant cells here will give rise to growths very similar to the orig- inal tumor. In the draining of the lymph through the lymph glands we would expect the first series of glands to be involved, /. e., to manifest evidences of metastatic growths. This is a very important diagnostic and prog- nostic sign. Almost invariably, in cases of malignant neoplasms, secondary tumors will be found in the lymph glands that are the first to receive the lymph from the neighbor- hood of the original tumor. When, however, the invasion has extended beyond the first to the second series of glands, then the case must be considered inoperable. Thus, in a case of malignancy of the forearm, the first glands to show metastatic growths will be the glands of the antecubital fossa. However, if the glands of the axilla also are involved, we must consider the dissemination of metastases too widespread to be relieved by surgical in- tervention. The primary function of a lymph gland is to check the spread of infection by draining infecting agents from the lymph stream, thus preventing them from entering the vascular system. The lymphatics can check cancer only for a time, and when the cells have passed the first series of glands and 40 CANCER have reached the second, this means that the first barriers have been passed and most prob- ably the invading cells have entered the blood stream. An invasion of the venous branch of the vascular system may take place in two ways, by the passage of the cancer cells from the lymph system into the veins, or by the direct invasion of the wall of the vein. In the first case numerous metastases will be formed throughout the lymphatic system and else- where. In the second case, when the malig- nant cells have found their way into the in- tima and have eroded this, an extension of the growth into the vein follows. If the vein involved is of any considerable size, a fatal hemorrhage is the issue. Whether the vein be invaded in one way or the other, metastatic growth will develop promptly in the lungs. It may be said that a growth manifesting hemorrhages has already involved the blood vessels, and therefore the blood stream has been burdened with intact cells that will pro- duce metastatic growths. An extension of cancer cells into the ar- terial system is less common than the inva- sion of the venous system. The arterial walls ofifer greater resistance to the invasion of the NATURE 41 growth. Cancer cells that primarily entered the lymphatic system are removed from the blood before it reaches the arteries. Cancer cells entering the arteries would be carried to the periphery, where they would be blocked by the capillaries, producing periph- eral metastatic growths. Veins, however, carry the cells centrally. Secondary growths even from primary peripheral tumors are more frequently located centrally than in the extremities. In the peritoneal and thoracic cavities, metastases may occur, independent of the lymph or blood supply. Thus, a cancer of the stomach may produce a secondary growth in the ovaries or rectum. Such secondary growths are due to the fact that cells become dislodged from the original growth through the movements of the viscera, or by surgical manipulation, or palpation. Such cells may be carried to a distant part of the cavity by the peritoneal or pleural fluid, and wherever they become fixed produce secondary tumors. Our advice to the clinicians, then, is to avoid all unnecessary manipulation of tumors suspected of possessing malignant character- istics or a tendency thereto. Recurrence. — From the point of view of 42 CANCER clinical medicine the salient feature of ma- lignant tumors is their tendency to local re- currence, that is, to appear, after their re- moval, in the vicinity of the original growth. The fact that tumor excisions have been ineffectual in promoting permanent cures must be attributed to this property, charac- teristic of malignancies. Obviously it is of little value as a diagnostic sign; however, a knowledge of the means by which recurrence takes place is of inestimable practical value to the surgeon and should form the basis of his technique. We know that a malignant neoplasm does not develop anew, but that cancer cells in a number of possible ways have been left intact in the organism and that these cells serve as a nucleus for a second tumor. The cancer cells migrating from the original tumor may have become fixed at some distance from the parent cell, and the new tumor due to these cells may be separated from the original w^ound by a margin of healthy tissue. As has been previously pointed out, cancer cells migrate principally through the lymphatic and venous systems. Elsewhere it has been shown that cancer cells disseminate throughout the organism NATURE 43 primarily by the lymphatic system. A dif- ferent growth of the primary tumor may ex- tend into the lymphatic ducts and proliferate there, checking the flow of the lymph. In the removal of all the tissues that microscop- ically appears to be diseased, the cells that have permeated the lymph system may be left intact and a recurrence will follow through these remaining cells. Particular attention, therefore, must be given in surgical technique not alone to the removal of the tissue that has the gross appearance of a cancer growth, but as well as to the excision of all tissue in the neighborhood that is known to be prone to the dissemination of cancer cells, and this tissue should be removed as widely as the anatomical relations to other parts will per- mit. This fact must especially be borne in mind in the surgical treatment of growths in organs or tissues that have a rich lymph sup- ply, as, for instance, the breast. By means of chains of lymphatic nodes the breast is inti- mately connected with the lymphatic glands of the axilla, the supra-clavicular glands, the mediastinal glands, and the glands of the op- posite breast. Malignant neoplasms of the breast which show a metastasis to any of these glands may be considered inoperable. If, 44 CANCER however, the case is operable, not only the neoplasm, but the entire breast with the fascia and pectoral muscles must be excised to pre- vent a recurrence due to disseminated intact cells. Cancer cells spread likewise to the venous system. If a growth manifests evi- dence of hemorrhage, in all probability the growth has eroded the walls of the vein. The destruction of the venous wall entails the en- trance of malignant cells into the venous blood, which means that metastases have taken place and that recurrence will follow, due to these metastases. Recurrence may be due also to cells dislodged from the primary tumor by mechanical manipulation, and this is particu- larly true in recurrence within the serous cavities, that is, within the thorax or the peri- toneum. We cannot impress too strongly upon the physician and the patient the risk following undue handling of malignant tu- mors. The therapeutic measures for the re- lief of inflammatory processes, such as mas- sage and rubbing, should never be employed where the tumor is suspected of being can- cerous, and the examinations of such growths should be undertaken with extreme gentle- ness and not repeated unless absolutely neces- sary. Furthermore, the cancer cells may be NATURE 45 disseminated by incising a growth to obtain a piece of tissue for examination. At times a rapid examination of the tumor by the frozen section method may be thought ad- visable, although positive conclusions cannot be drawn from its results. In cases of this kind, when practicable, a piece of tumor should be removed by cautery, rather than by the knife. Authorities who have had expe- rience in handling cancer patients with and without operations are agreed that metastases in recurrence can be checked more rapidly in patients where the tumors have not been ex- cised or cut into for microscopical examina- tion, than in cases that have been operat' upon. It would seem, therefore, that surgical interference — if not based upon an intimate knowledge of the means by which cancer cells disseminate, causing recurrence, and of the methods of stimulating cancer cells to proliferation — is apt to be ill-advised and attended with unfortunate results. Experimental work upon the transplanta- tion of tumors in mice, from one individual to another, have shown that a tumor may be produced in the second host by the implan- tation of intact cells subcutaneously. There- fore, all that is needed to produce a second 46 CANCER tumor is an inoculation with the living cells. Whether cancer may be transplanted from one human being to another in a similar man- ner has not been proved, but statistics show that the growth may be transferred from one locality to another within the same individual. As applied to the methods for treatment of cancer, observation implies that cancer cells coming in contact with other organs will pro- duce secondary tumors. This is particularly true of sloughing cancerous tumors. The roof of the urinary bladder is very apt to be infected from a cancer at its base. An in- structive illustration of this point in connec- tion with another portion of the body came under the observation of one of the authors recently. The patient, a man of middle age, complained of severe penetrating pain in the right epigastric region. The cause of the pain was diagnosed by the surgeon as cholelithiasis. During the operation, undertaken without a suspicion of a malignant neoplasm, a cancer was found in the upper right epigastric re- gion. A piece of tissue was removed for examination, and the wound came in contact with the freshly incised growth. When it w^as known that the abdominal growth was malignant the wound was sutured and the NATURE 47 patient was transferred to an institution de- voted exclusively to cases of cancer. A short time after his entrance a growth developed along the abdominal scar and spread very rapidly. Moreover, new vigor was appar- ently given to the intra-abdominal growth, which within a short time could be palpated with ease; and at autopsy it was found to have invaded the small intestines, and by pressure upon the spinal cord to have produced paral- ysis and complete anesthesia of the lower extremities. Further, the use of a trocar in tapping or exploring malignant tumors is in- variably productive of the development of secondary tumors along the line of entrance of the instrument. The greatest number of recurrences due to implantation of cancer cells in healthy tissue are reported in the ex- cision of malignant growths of the female genito-urinary tract. Cancer of the uterus is probably the most common form of the mal- ady in the female sex. The removal of the tumors of the uterus by vaginal hysterectomy is frequently followed by the development of the tumor in the scar in the apex of the va- gina, or the sides of the vulva (in cases of narrow vaginal orifice), when incisions are made at these points to afford more space for 48 CANCER the removal of the uterus. It is practically impossible to keep these cut surfaces from touching the cancerous growth and thus to avoid an implantation of the cancer cells in the vagina. The use of the cautery, however, to destroy as much as possible of the growth before its removal, although it does not ob- viate all possibility of implantations, never- theless may diminish the chances of infection through contact of living cancer cells with healthy tissues. The cells that remain in the wound after excision probably proliferate at once. How- ever, some time will intervene before the presence of the new growth can be demon- strated. The time that must elapse without the development of a recurrence, before the case can be considered cured, differs accord- ing to different authorities. Formerly it was considered that a lapse of three years without a recurrence was indicative of an effectual cure. Other authorities have placed the limit at two years, while it is now generally ac- cepted that recurrence may take place within five years (or more) of the operation. Ulceration is not pathognomonic of malig- nant tumors, and therefore as a diagnostic sign it has little value. Innocent tumors may NATURE 49 ulcerate and malignant tumors may remain sterile. Malignant tumors ulcerate when they are exposed to injury or irritation, and in this mechanical production of the ulceration be- nign tumors are similar to the malignant. A peripheral hyperplasia with a central hypoplasia leading to degeneration is charac- teristic of a rapidity of growth. A malignant tumor depends for its nourishment not upon special vascular and lymph supply to itself, but principally upon the blood vessels in the stroma of the tissue invaded. Hence the periphery of the tumor receives a rich sup- ply of nutritive material. When, however, the blood vessels become incorporated in the growth, their tissues are invaded and de- stroyed, which means that the central portion of the tumor degenerates owing to a failure of nutrition. The degeneration may take the form of an active necrosis, or the form of a quiet necrosis, or necrobiosis. On the other hand, sarcomata may undergo a calcareous degeneration or a myxomatosis. In the latter case the greater portion of the tumor assumes a jelly-like appearance and is surrounded by a thin wall of tissue. Cachexia is not invariably present, particu- larly in sarcomatous cases. It is a late con- 50 CANCER stitutional development, resulting from the effect of the tumor upon the organism as a whole. The time of the development of the cachexia depends particularly upon the loca- tion of the tumor. Thus a neoplasm of the stomach directly interferes with the supply of nourishment to the body, so that the ap- pearance of the cachexia takes place in the earlier stages. Peripheral tumors, however, for instance, of the breast, may attain an enormous size before the patient develops a cachectic appearance, and in fact the cachexia may never take place. In peripheral tumors the factors that play the greatest part in pro- ducing the cachexia are ulceration of the surfaces with hemorrhage leading to a septic condition. Cachexia due to carcinomata that slough rapidly will develop more rapidly than in any other conditions; for instance, a carcinoma of the cervix of the uterus is char- acterized by its early and continuous slough- ing. This sloughing may be the cause of a secondary infection producing the cachexia. It would seem, therefore, that in treating can- cer patients, inasmuch as it is necessary to stimulate the vitality in healthy cells, cachexia must be warded off, and therefore all exter- nal tumors or growths must be kept from NATURE 51 ulcerating. This applies to any growth, whether it involves the cervix of the uterus or some skin manifestation. As to the means of preventing ulceration and secondary infec- tion, see chapter on Antiseptics. The cause of the cachexia is either the absorption of catabolic products of the tumor growth and its consequent metastasis, or, secondarily, the interference exerted by the tumor upon the functions of the essential organs. The entrance of cancer cells into the blood and lymph sys- tem takes place early, and a general dissemi- nation of these cells can be detected by an analysis of the blood before cachexia devel- ops. A degeneration of the cancer growth leads to a secondary infection, and the effect of this upon the blood stream is similar to that of any infection. Our observations upon the changes in the composition of the blood lead us to believe that there are other prod- ucts concerned (of which little is known), that find their way through the tumor into the blood stream, and these products may be very important factors in the etiology of the cachexia. The interference exerted by the growth upon the essential organs may be me- chanical, that is, due to pressure, erosion of its walls, and so on; or it may be due to the 52 CANCER absorption of toxic products, elaborated by the neoplasm. The blood changes in malignant disease take the form characteristic of a secondary anemia, varying in intensity. The produc- tion of the anemia may be attributed to a number of causes, principal among them be- ing: (i) the action of the toxic products of the tumor upon the organs concerned in blood production; (2) secondary infection; (3) a disturbance of the organs by the pri- mary growth or its metastases. Ordinarily the red cell count is reduced. Variations from this statement, that is, a normal count or an increased count, must be attributed to a concentration of the blood, and is not a fa- vorable symptom. The percentage of hemo- globin is subnormal, and this may take place even when the red cell count is normal. The number of white cells, w^hen increased, usu- ally indicates an infection rather than any characteristic efifect of the tumor. Hemor- rhage and rapid growth and the formation of metastases are also important factors in pro- moting leukocytosis. The cachexia is gradual and progressive. The patient assumes a straw-yellow color, which must be attributed at least to a dimin- NATURE 53 ished hemoglobin production or a change in the composition of the hemoglobin. The pain is not always localized in a growth of the gastro-intestinal tract, but it may partake of the nature of what Head calls ''Referred Pain." Rheumatic symptoms give rise to what has been called rheumatic diathesis. When the pains are due to an ulceration in the secondary infection, they are more potent in producing pain than the growth itself, and therefore there is every need of keeping the wound clean. In non-ulcerated cases fever is usually absent, or there may be a slight in- crease in temperature due to the absorption of toxic products. Some of the cases termi- nate in coma. The majority, however, die in a condition of general cachexia. CHAPTER II Pre- Cancerous Conditions The overwhelming percentage of recur- rence of cancerous lesions following opera- tive treatment is regretfully attributed by the clinician to the fact that the malignant nature of the lesion is recognized too late, and that when it comes to the surgeon it has already advanced to the inoperable stage. Hence the operative treatment of neoplasms is far from satisfactory. In this direction it can be much improved. This tendency to recur, as we have shown elsewhere, is characteristic of a malignant neoplasm and due to its ability to form metastases. If, therefore, it were possible by analytical and symptomatic means to foretell the development of a malignancy, or the transformation of a benign into a malignant growth, surgical treatment of cancer at this stage would be attended with much greater success. The recent advances in pathology, coupled 54 PRECANCEROUS STATE 55 with the careful collection of statistics, have rendered possible this desired end. There is no phase of pathology of greater profit to the general clinician and surgeon than the study of the so-called pre-cancerous lesions. By a pre-cancerous lesion we understand not an incipient cancer, but a benign lesion or growth of the type that most frequently de- velops malignant characteristics. Although such a lesion, if left alone, may never become a cancer, it should be looked upon with grave suspicion by the surgeon. We realize that in making the above state- ment we are simply reiterating what has been written over and over again, particularly in the publications of the last ten years; but the subject is such an important one, and is so forcibly brought to the attention of any one who studies the whole cancer problem in a serious manner, that there never seems to be any likelihood of the statement being made too often. It should also be constantly borne in mind that statements like the above refer to a lesion or lesions which are supposed to be clear and well-marked entities, and that beyond them the rest of the system is free from cancerous invasion. Recent works, however, through new meth- 56 CANCER ods of technique at the present time coming into use in the X-ray laboratories, the new advances made in the chemical examination of the urine and the blood, enable us to clas- sify these conditions somewhat more clearly than would have been possible ten years ago. They can be classified into those having ex- ternal and internal lesions ; they may also be classified into those where the whole system, through lack of time or opportunity or con- venience, has not been as thoroughly exam- ined and mapped out as the modern methods of diagnosis would admit. A second class in which, the presence of these lesions having been observed, a thorough and systematic in- vestigation of the whole system has been made; and a third class, which we may be among the first to recognize, which may be pre-cancerous, in which no- particular lesion either internal or external can be diagnosed, but in which there is a bad family history of the frequency of cancer occurrence, and in which is found a marked modification in the sulphur metabolism, as told by the examina- tions of the blood and urine. For patients of this class we should insist on examinations being made at not far distant intervals from one another, and the necessity, as far as prac- PRECANCEROUS STATE 57 ticable, of such individuals leading a life where the tissue metamorphosis is kept in as near a proper condition as possible, together with the administration more or less con- stantly of internal medication, such as the indications surrounding any individual case would seem to require. This is referred to again in the chapters on treatment, farther on. Such cases are very apt to show changes in the sulphur metabolism similar to those occurring in gout, where the nitrogen metab- olism is alone affected, and in which uric acid is the prominent characteristic and the patient is treated accordingly, but in members of the class to which we refer, the sulphur and not the uric acid seems to be the element the changes in the metabolism of which are the most prominent. This, too, brings us to a consideration at this point of another element which is apparently more or less involved in the changes in the metabolism due to cancer, and that is potash. An able treatise has been written on that work by Ross, "Cancer, Its Genesis and Treatment," London, 1912; and, recently, one by Dr. L. Duncan Bulkley, "Cancer, Its Cause and Treatment," has called attention to changes in this element. It is through a desire to dwell more carefully 58 CANCER on investigations personally carried on by us that the changes in potash metabolism in can- cerous conditions are not more frequently mentioned. We consider them of less im- portance than the sulphur; but later on we may publish our observations on the metab- olism of potash. Referring now to the second class — in which some lesion has been observed either exter- nally or internally, and in which a careful examination of the whole system has been carried on — among the lesions occurring in this class may be mentioned apparent fibrous tumors of the breast or of the uterus, old chronic inflammatory conditions of the pros- tate, ulcers of the stomach, and on the skin or mucous membrane such lesions as frequently recurring herpes, and patches of chronic seborrhoea, or eczema. These should all be treated by excision. X-ray, or, according to conditions surrounding any given case, by proper measures, either local or general, to do away with any chronic inflammatory proc- ess that may be present. There still remain those cases of the first class mentioned, in which chronic lesions exist which may become cancerous, but on account of various reasons it is practically PRECANCEROUS STATE 59 impossible for the attendant to use all the refinements of diagnosis which might in other cases be available. Under such circumstances the attendant should carry out as many of these refinements as possible, according to the circumstances surrounding any given case. The above statement is so simple that it hardly seems necessary to dwell on it, but clinical experience seems to indicate that even at the present time thorough diagnostic measures, even when available, are not employed as frequently as they should be. To illustrate: If a small tumor of the breast presents itself, and it is impossible to obtain careful X-ray pictures taking in the thorax, the liver, the stomach, and the gall bladder, at least a careful examination can be made of the urine and the blood, particu- larly as regards the sulphur content, and the prognosis before operation modified some- what according to the conditions that may be found. Even from careful examination of these not only will it be possible to modify the prognosis, but the results of such findings may often have some modifying efiPect upon the nature or extent of the procedures, opera- tive or otherwise, to be undertaken. PART III DIAGNOSIS OF CANCER CHAPTER I Details of Methods of Sulphur Find- ings IN Blood and Urine The blood as a circulating fluid comes into intimate contact with the cells of all the tis- sues and organs, and between the blood and the cells there is an exchange of nutritive material and catabolic products. We would expect, then, that the products from any par- ticular abnormality would find their way into the blood stream, and there could be detected. The blood of cancer patients shows concen- tration of constituents that are not paralleled by any other pathological condition. Now, gout is characterized by an increase of the uric acid content of the blood. Chronic in- terstitial nephritis produces an increase in the urea, uric acid, and creatinin of the blood. Diabetes, on the contrary, does not affect the 60 SULPHUR FINDINGS 6l nitrogenous constituents, but is characterized by an increase of the sugar content. None of the constitutional pathological lesions thus far studied produce any effect that can be simu- lated by that of the malignant tumor. A ma- lignancy in all the cases examined has pro- duced an increase in the non-protein nitrogen, which increase cannot be accounted for by any increase in urea, uric acid, or creatinin; nor is it an amino-nitrogen compound. Diseases of the liver that interfere with the activities of this organ will present an increase of the amino-nitrogen, owing to the fact that the liver no longer can deaminize amino acids. Further, carcinomata manifest an increase in the total sulphur content of the blood. In these conditions the proportion between the non-oxidized and the oxidized sulphur of the blood stream is disturbed with a proportionate increase of the former. Methods Used for Analysis of the Blood The total non-protein sulphur of the blood in non-carcinomatous conditions may be stated, from our observations, to be an aver- age of 3.6 milligrams per 100 c.c. of blood. Now, of this total sulphur some 80 per cent to 85 per cent is in the form of sulphates. 62 CANCER The remainder is non-oxidized sulphur. In carcinomatous conditions the total non-protein sulphur rises to two or three times the normal figure, while the total sulphates remain at the normal level. It appears, then, that the increase in sulphur is due to an increased amount of non-oxidized sulphur in the blood, not due, however, to the proteins. For the methods of calculating the non- protein nitrogen, non-protein sulphur, urea, uric acid, and creatinine of the blood we refer the reader to reliable text-books on the chem- istry of the blood. Concerning the urine, all previous investi- gations conducted upon the question of sul- phur metabolism in cancer conditions have utilized the Salomon-Saxl reaction for neu- tral sulphur in the urine. This consists in converting the ethereal sulphates in the urine by boiling with hydrochloric acid into inor- ganic sulphates and then precipitating the total sulphates with barium chloride, the fil- trate from this reaction containing the unoxi- dized sulphur. To the total filtrate hydrogen peroxide was added and the. mixture boiled and then upon standing the precipitate was thrown down, which precipitate represented the total neutral sulphur in the form of sul- SULPHUR FINDINGS 63 phate. This precipitate was allowed to settle out in a conical graduated tube, and from the amount of precipitate formed a positive or a negative reaction was reported. A most con- scientious and comprehensive account of this method, with a very complete bibliography of the subject, has recently been published by Max Kahn, Journal of Cancer Research^ July, 1917. Kahn's conclusions, as given in the article referred to above, are as follows: ^'In car- cinoma there is generally observed an in- crease in the percentage of neutral sulphur in the urine. This may be ascribed to a lessened power of oxidation or to an increased destruction of tissue with the failure of the organism to oxidize the broken-down prod- ucts to the sulphate (oxidized) state. The colloidal nitrogenous substances are increased in the urine of cancer patients, as well as in the urine of anemic, diabetic and syphilitic individuals, etc. It has been the experience of the author (Kahn) that the determination of this fraction in conjunction with the Salo- mon-Saxl test for so-called 'neutral sulphur' is of great aid in the diagnosis of carcinoma if both of these tests are positive. A nega- tive result with either the Salkowski-Kojo 64 CANCER test or the Salomon-Saxl test detracts very much from the significance of the results so far as carcinoma is concerned." Some of our own cases have also shown, in addition to the excess of neutral sulphur, an excess in the nitrogen products in the urine. But we do not consider this latter so much indicative of carcinoma as of nephritis, which may or may not be the result of the carcinoma. Our own investigations into the sulphur metabolism in carcinomatous conditions at first were based upon the Salomon-Saxl reac- tion, but it was found that this reaction was unreliable, because in all conditions the hy- drogen peroxide did not completely oxidize the neutral sulphur; and, moreover, it was found difficult to obtain a sample of hydro- gen peroxide which did not contain an im- purity that would give a precipitate with the barium chloride. We therefore adopted the Benedict method for total sulphur and the Folin technique for the total and inorganic sulphates. Total Sulphur. — To lo c.c. of urine are added 5 c.c. of the Benedict sulphur reagent in an evaporating porcelain dish. The mix- ture is carefully heated until it solidifies, and is then heated to the maximum intensity of SULPHUR FINDINGS 65 the Bunsen burner for ten minutes until it becomes completely black. After the dish has cooled, this black residue is dissolved in 20 c.c. of 1-4 hydrochloric acid, and 10 c.c. of 10 per cent barium chloride are added. The precipitate is filtered oflf in a Gooch crucible or through filter paper and very carefully washed, and the amount of precipitate is de- termined by ashing and weighing. For the Sulphur. — The urine is first diluted with an equivalent amount of 1-4 hydro- chloric acid. For this purpose one takes 25 c.c. of urine, and after boiling for twenty to thirty minutes, the mixture is cooled and water added to 150 c.c, then 10 c.c. of 5 per cent barium chloride. The precipitate is fil- tered and weighed as for the neutral sulphur. Inorganic Sulphates. — To 25 c.c. of urine are added 20 c.c. of 1-4 hydrochloric acid and the volume made up to 150 c.c. with water. Then 5 c.c. of 5 per cent barium chloride are added and the precipitate, after at least one hour settling, is filtered ofif and weighed. These methods give the compounds of the sulphur content of the urine as grams of SO3, and knowing the total volume of urine, it is best to express the output of sulphur as the amount excreted in twenty-four hours. The 66 CANCER total sulphur minus the total sulphates gives the total neutral sulphur. If it is desired to divide the neutral sulphur into two groups, the easily oxidized and the difficultly oxi- dized group, one should take the filtrate from the total sulphates, evaporate that down over a water bath to about 25 c.c, and then add 10 c.c. of ferric chloride, and heat over a free flame for fifteen minutes. The additional sulphur obtained by this technique over the total sulphates represents the total neutral sulphur in the easily oxidized group. By subtracting the inorganic sulphates from the total sulphates we obtain the ethereal sul- phates. Subdividing the neutral sulphur into two groups enables us to say whether the liver is involved in a carcinomatous condition or not. It is the function of the liver to dilute the taurine into taurocholic acid which, com- bined with sodium and potassium, is excreted in the bile. A lesion of the liver of such an extent as to inhibit the functions of that organ will necessarily imply that the taurine will not be synthesized into the corresponding acid, and therefore it will not be removed from the blood stream. In such a condition an abnormal quantity of taurine will pass into the urine. This will mean an increase in the SULPHUR FINDINGS 67 neutral sulphur and an increase in the diffi- cultly oxidized group, whereas in carcinoma we find an increase in the easily oxidized group. Too much stress, however, should not be placed upon the distinction, because a car- cinoma of any extent will form metastases in the liver and thus interfere with the problems of its function. Urinary Sulphur. — In the chemical inves- tigations of metabolism, workers have gen- erally confined their attention to the nitrog- enous constituents of the urine; the sulphur, however, demands equal consideration. The sulphur occurs in the urine in two forms, the oxidized sulphur, which is composed of the inorganic sulphates and the organic sulphates, and the unoxidized sulphur, composed of a number of constituents that are divided into two groups. Of the first, the easily oxidized group, cystine and potassium sulpho-cyanate are typical examples; of the difficultly oxi- dized group, taurine is the salient component. The unoxidized group is more commonly known as the neutral sulphur. Folin has shown that the oxidized group consists of products of exogenous metabolism, while the neutral sulphur contains the products of en- dogenous metabolism, that is, of tissue break- 68 CANCER down. The neutral sulphur, then, would be comparable to the nitrogen of endogenous nitrogenous products, as creatinine, creatine, etc. Our own experiments upon feeding pa- tients with sulphur-containing foods and sul- phur-free foods has shown that the amount of neutral sulphur is independent of the sulphur content of the diet. The urine of carcinom- atous cases is characterized by the fact that they show an increase in the neutral sulphur compared to the oxidized sulphur, but the total amount of sulphur excreted is dimin- ished. Under normal conditions, a person engaged in moderate activity excretes about 3 grams of total sulphur estimated as SO3 in twenty- four hours. Of this, 5 to 13 per cent is composed of neutral sulphur, about equally divided between the easily oxidized and the difficultly oxidized groups. Of the oxidized sulphur the inorganic sulphates stand to the organic sulphates in the ratio of 10 to I. This balance between the sulphur components is disturbed in carcinoma. The total excretion of sulphur drops to below 2 grams in twenty-four hours. The proportion of neutral sulphur is increased to from 20 to 30 per cent, or even higher, of the total sulphur. The relative amount of neutral sul- SULPHUR FINDINGS 69 phur is not influenced by the sulphur content of the diet. However, X-ray treatment, as long as a growth is submitted to the emana- tion, greatly increases the output of neutral sulphur, but this returns again to its former level when the treatment has ceased. So, too, the surgical removal of the growth is appar- ently accompanied by a proportionate drop in the amount of neutral sulphur excreted. With the data at our disposal we are con- vinced of the invariability of these findings. But, however, the data will not permit speculation at the present time, regarding the nature of the chemical changes in a carci- nomatous cell the cytoplasm predominates in amount over the nucleus, and consequently inasmuch as sulphur proteins predominate in the cytoplasm we would expect an increased output of endogenous sulphur metabolic products. At the present time plans are be- ing made for a histo-chemical study of the changes in tumor growth, and it is hoped that these investigations will throw more light upon the origin and the significance of the increased neutral sulphur output. However, at the present tifne these findings have been sufficiently substantiated to constitute a valu- able aid in diagnosis. 70 CANCER After the removal of a malignant tumor, it has been noted that the non-protein nitro- gen and the sulphur return to their normal level. It would seem, therefore, that they are directly the products of the tumor metab- olism, and not products of the effect of the tumor upon the general system, as in cachexia. The exact chemical nature of the compound or compounds whose occurrence in the blood gives rise to this abnormal amount of nitro- gen and sulphur is at the present time an unsolved problem, but we are justified in considering the same as a metabolic product of the tumor growth, or a toxin invading the general circulation, and thus causing metas- tases. It would seem, therefore, that if this product be a toxin predisposing other tissue cells or other hosts to a malignant formation, the inoculation of other individuals with the carcinomatous blood would give rise to tumor formation in the new hosts. It has been found that in animal experimentation this fact has not been substantiated. However, we must not go too far in our deductions from animal experimentations, because it has been found that animals will not always develop consti- tutional lesions characteristic of the human organism. Moreover, if this compound be a SULPHUR FINDINGS 71 predisposing toxin, then carcinomata may be inherited, in a loose sense of the word; that is, the toxin may pass from the placental to the foetal circulation, predisposing the foetus to a malignant tumor formation at the in- tervention of the secondary cause. Such a conception coincides with observations upon carcinomata transmission in breeding mice. (See chapter on Heredity.) By successive breeding with aliens, that is, with non-infected animals, the vitality of the toxin may be greatly decreased, and consequently may be entirely bred out. CHAPTER II Diagnosis by Chemical and Bacteriolog- ical Means The general statement frequently made by the surgeon, that every neoplasm, whether malignant or benign, should be removed sur- gically, deserves serious consideration. It is indeed true that every tumor, whose surgical removal would not interfere with the func- tions of any vital organ, may be excised with impunity. However, inasmuch as the treat- ment of cancer should not end with the ex- cision of the tumor, there is every need to carefully diagnose a malignancy, and upon a positive diagnosis to institute an anti-car- cinomatous or anti-sarcomatous treatment. Many pathologists look upon neoplasms as potentially malignant, and therefore advise their removal. However, where we have an involvement of a vital organ, excision becomes impossible, and we must resort to all the means at our disposal to substantiate the ex- istence of a malignant neoplasm. Moreover, LABORATORY DIAGNOSIS 73 inasmuch as the treatment of cancer is largely prophylactic, an early diagnosis is very essen- tial. Where the growth is not removed by surgical means, we cannot apply a means of diagnosis based upon the morphological char- acter of the cells, but we are forced to adopt chemical, and in some cases bacteriological, methods for the corroboration of the clinical findings. Neoplasms of the Gastric Intestinal Tract Stomach. — The work heretofore done by pathologists and surgeons in connection with the cases of gastric cancer which have been cured, or have resulted in any considerable prolongation of life, has only been possible in those cases in which an early diagnosis was made, thus permitting a removal of the neo- plasm before it had become an extensive process. In gastric conditions we are pre- sented with the problem of differentiating a malignant neoplasm from such conditions as gastric ulcer, chronic dilatation of the stom- ach, chronic gastritis — conditions which in many ways closely simulate a malignant tumor. 74 CANCER General Considerations. — ^When a gastric malignancy has become thoroughly estab- lished in the general appearance of the pa- tient, there is the appearance of hopelessness characterized by a dullness of the eye, sunken cheeks, and listless posture, with a tendency to collapse upon any physical exertion. In addition to these there will be noted a loss of weight, scaly skin, an absence of fatty depos- its about the body, and a scaphoid appearance about the abdomen. The general picture re- sembles that of anemia, with a grayish or yel- lowish tan coloration of the skin. The mucous surfaces of the mouth are pale and parched. The tongue becomes heavily coated and shows well-marked fissures and papillae, and the breath has the odor of gastric fermentation. Decayed teeth and pyorrhoea alveolaris are not infrequently found to accompany the gastric malignancy. The mouths of such patients usually contain parasites, chief among which are amoebae and pathogenic bacteria. In the late stages of the disease edema will sometimes occur beneath the eyes. The fer- mentation in the stomach gives rise to a growth of multitudes of micro-organisms, which will be taken up, and on their passage through the kidney produce a secondary LABORATORY DIAGNOSIS 75 chronic nephritis. Externally there may be evidence' of metastases in the lymph glands, particularly in the left supra-clavicular space. Metastases in the abdominal cavity give rise to ascites, and the composition of the fluid may be characteristic of this disease. The liver may be enlarged, owing to secondary growths. Patients with gastric malignancies very frequently manifest nervousness, which in most cases is concerned with their great loss in weight, deficiency of strength, and the inability to take food. In 6 per cent of the cases the neoplasm has been found to involve the pylorus, the antrum, and the lesser curvature. The posterior wall has been involved in about 9 per cent and the anterior wall in about 2 per cent. Chemical Examination.— The chemical fea- tures of the gastric secretion are not sufficient to serve as a basis for a positive diagnosis, but combined with the clinical history they make an invaluable aid in establishing or excluding the presence of a malignancy. The most salient factor of the gastric se- cretion in this condition is the absence of free hydrochloric acid. This, however, is not characteristic alone of carcinoma, inasmuch as it is found also in atrophic and chronic 76 CANCER gastritis. It has been suggested that the ab- sence of the hydrochloric acid is due to the combination of this acid with a compound secreted from the malignant growth. From a number of cases that we have followed, it is interesting to note that very frequently the absence of free hydrochloric acid is accom- panied by diminished content of the blood. Acid Constituents. — Before an estimation of the acidity is made, the gastric contents should be filtered. For the free acidity we use 2 c.c. of the fluid titrated against N/50 sodium hydroxide with Topfer's solution as an indicator. For the total acidity phenol- phthalein is employed, titrating the same quantity of contents with alizarin as an in- dicator, and subtracting this from the total acidity against the combined acidity. For the examination of the gastric contents the earlier investigators employed the Ewald test meal and the retention meal. A meal consisting of two slices of bread, unbuttered, or dry toast were given to the patient with 200-300 c.c. of fluid, water or unsweetened tea. One hour afterwards the total contents of the stomach were aspirated and the con- tents analyzed for the various components of the acidity, the presence of blood, and the LABORATORY DIAGNOSIS 77 peptic activity. These analyses furnished the clinician with an idea of the secretory func- tions of the stomach. The motility of the organ was determined by giving a meal con- taining articles of food poorly digested, such as raisins, and twelve hours afterwards re- moving the total contents of the stomach. Under these conditions only an inaccurate idea of the stomach's secretory or motor pow- ers can be secured. Moreover, these tests are accompanied by great distress to the patient, and inasmuch as these types of cases are al- ready in a very weakened condition, we would not advise these means of chemical diagnosis. The method which in our hands has yielded the best results is as follows. The evening before the test is to be performed a duodenal tube is swallowed. The patient lies upon the left side, until it is judged that the tube has entered the stomach. Thereupon the patient lies upon his back, and then upon his right side. The following morning it will be found that the tube has entered the duodenum. This will be indicated by the golden yellowish ap- pearance of the fluid aspirated and its alkaline reaction to congo red. Immediately before the performance of the test another tube is dropped, with the patient sitting upright. 78 CANCER The swallowing of the tube may be assisted by the ingestion of a small quantity of water. About 200 c.c. of water are given to the pa- tient, and a portion of the contents of the stomach and duodenum removed by a syringe for fifteen minutes, until the stomach is emp- tied. The fluid thus obtained is analyzed for its acidity, enzyme activity, and for the pres- ence of food remains or pathological constitu- ents, such as blood or carcinomatous cells. If the pylorus is patent, the duodenal tube will easily enter the small intestines. In cases of pyloric stenosis the duodenal tube may be dispensed with. The Microscopic Appearance of the Re- tention Contents. — To obtain the retention contents of the stomach the total fluid in the stomach is removed before the giving of water. This is done by removing the contents while the patient lies upon the right side, then upon the back, and finally upon the left side. If the pylorus is not obstructed the retention contents will be clear. It may vary in vol- ume from a few cubic centimeters to a liter; frequently portions of poorly digested food will be removed, intermixed with mucus. If blood is present' the aspirated fluid will be dark brow^n or coffee color. Not infre- LABORATORY DIAGNOSIS 79 quently a discoloration due to bile will be obtained. In the majority of cases the fluid will have a rancid odor, due to volatile or- ganic acids. Putrefactive odors may be due to a sloughing of the cancer tissue, or the breaking down of blood, or the penetration of foreign material through a fistula. Mucus, in a tough, stringy form, containing particles of food, or the cancer tissue will be easily obtained. Where the mobility of the stom- ach is very low, and the free acid deficient, the food particles will be in large amounts and poorly digested. In spite of the clinical symptoms mentioned above as regards the appearance of the pa- tient, loss of weight and appetite, extensive cancer infiltrations of the stomach, intestines, and both are occasionally met with at opera- tion, where the general appearance of the patient presents no difference from that of perfect health. Such cases may, however, give a history of having very recently had symptoms of intestinal irregularities of some sort, justifying the surgeon in performing an immediate exploratory operation, as the symptoms may simulate gall bladder disease or appendicitis. It would be extremely inter- esting to note in these cases whether sulphur 8o CANCER examination of the urine and blood would not show an increase in the percentage of neutral sulphur, as we believe would be the case. So far we have not had an opportunity to verify this statement. The type of case just men- tioned is comparatively rare. CHAPTER III Diagnosis of Malignancies of the Stomach The problem presented in diagnosis of a malignant growth of the stomach is to dif- ferentiate such a condition from an anacid gastritis that is of the interstitial or paren- chymatous type and a gastric ulcer. It may be said that gastric cancer is found prin- cipally in individuals of advanced age who give no history of chronic dyspepsia. This is most probably due to the fact that a chronic dyspeptic assiduously avoids food of a quality that is indigestible, or of a quantity beyond the capacity of the gastric digestion, and therefore the irritating action of indiges- tible food or of chronic overeating is obvi- ated. Gastric malignancies are observed more frequently in individuals with the normal habitus than in individuals with a habitus enteroptoticus. The onset of the disease is more rapid and more acute than in gastritis 8i 82 CANCER and more persistent than in ulcer. The pain associated with this condition is spon- taneous and is found to be independent of the intake of food. It is referred to the epigastrium and is generally described as a gnawing or boring sensation. The vomiting of the stomach contents after eating is a fre- quent, but not always a characteristic sign, p? Etiology. — Gastric carcinoma is more fre- quently observed in men than in women. In men the most frequent cause is alcoholism. In both sexes chronic overeating or the in- take of food difficult of digestion may be a sufficient secondary cause to invoke a malig- nancy. In a small percentage, patients with gastric cancer give a previous history of ulcer. Trauma, particularly of the character associated with occupational diseases, may lead to a malignant formation. If the onset of the gastric affection can be definitely dated within a year or eighteen months following injury, it is safe to say that the etiological factor in this particular case was the trauma. Gastric ulcers, if not relieved surgically or by dietetic means, degenerate, and in this degeneration assume malignant characteris- tics; hence, the pre-cancerous lesion that can be definitely associated with the development STOMACH 83 of a malignancy is a gastric ulcer. (See chap- ter on Precancerous Lesions.) The most frequent sites of gastric malig- nancies are the lesser curvature, the cardia, and the pylorus. It may be interesting to note that gastric ulcer also develops in these areas. Inasmuch as the only satisfactory re- lief of neoplasm of the stomach is surgical procedure, it is very essential to locate the position of the growth. In general, a malig- nancy of the stomach, no matter where its location, will be observed to have the same effect upon the composition of the blood and urine as malignancy in other areas. In con- nection with sulphur metabolism in carci- nomatous conditions, it is interesting to note that several years ago Schmidt of Vienna adopted as a differential sign the failure of sulpho-cyanate reaction in the saliva. How- ever, too much stress cannot be placed upon this qualitative test. A more certain diag- nosis can be arrived at from a knowledge of the gastric contents. Differential Diagnosis. — Inasmuch as gas- tric ulcer may be considered a pre-cancerous lesion, it is important in this connection to consider means of detecting an ulcerating process in the gastric mucosa. An ulcer of 84 CANCER the chlorotic type is of a hematogenous origin; /. e.^ it is subsequent to circulatory changes, it has primarily a low hemoglobin index and a low red cell count. The chlorotic type of ulcer is more com- monly found in young girls than in other classes of patients. Ulcers of this type leave no after-effects, and no observations have been made of the degeneration of such an ulcer into a malignancy. An ulcer, however, of a mechanical origin or subsequent to a syphilitic or a tuberculous infection is to be considered liable to degeneration. Ulcers of this type are characterized by stasis of food in the stomach, a hyperacidity of the contents, and an occasional trace of blood (all types except chlorotic). The pain commonly called epi- gastric is referred to the epigastrium and may radiate upwards and to the back. A large number of cases of ulcers that have shown recurrence have been studied for disturbance in sulphur and nitrogen metabolism, and it has been found that they produce no effect upon the concentration of the non-protein nitrogen and sulphur of the blood and urine, until they become malignant. The degeneration of these ulcers into neo- plasms is always of the carcinomatous and not STOMACH 85 of the sarcomatous type. Such a degenera- tion can be detected first by a gradual de- crease in the hyperacidity of the gastric contents, and secondly when the neoplasm has become definitely established by the propor- tionate increase in the neutral sulphur of the urine. Inasmuch as this degeneration may take place unaccompanied by pain, and there- fore without the patient's knowledge of his condition, we would recommend the study of the composition of the urine and gastric con- tents for some period of time following the disappearance of pain or the relief of an ulcerative condition. In a volume of this type naturally we cannot dwell too long on every minute symptom associated with these conditions, but on account of the increasing frequency with which cancer of the stomach is commencing to be found, we think it ad- visable to speak more fully than on some other conditions mentioned. Gastric carcinoma may be differentiated from an anacid gastritis by the composition of the gastric contents or by the sulphur par- tition of the urine. Anacid gastritis, like car- cinoma, is characterized by a low acidity of the gastric contents. In this condition, how- ever, we do not find blood by chemical 86 CANCER methods, nor do we find lactic acid or the Boas-Oppler bacillus. Gastritis produces no changes in the body fluids, as the blood or urine, and this fact is of vast importance in dififerential diagnosis. Neoplasms of the Pancreas. — The pancreas is intimately associated with carbohydrate metabolism. In this connection its chief func- tion consists in the removal of diastase or starch-splitting enzymes from the blood and the secretion of these enzymes in the duode- num. A malignancy at the head of the pan- creas will inhibit the activity of the cells, and therefore a failure to eliminate diastase from the blood into the duodenum will follow. This can be detected by an increase of the activity of the diastase in the blood and a decreasing ac- tivity in the duodenal juice ; for the calculation of these enzyme activities, the procedures we have found most available are the methods for the diastatic activity of the blood and duodenal juice as described by Killian and Myers. The activity in the blood in these conditions will rise to twice the normal, with a consequent hyperglycemia. A failure to produce lipase of the pancreas will be indi- cated by an abnormal quantity of neutral fat in the feces. A neoplasm of the neck of the STOMACH 87 pancreas may by mechanical pressure upon its duct restrict the passage of the pancreatic juice into the duodenum. In these cases effects similar to those noted above will be observed. By the methods at our disposal it would be impossible to localize the neoplasm to either the head or the neck of the pancreas. However, such a differentiation is of no great value, inasmuch as surgical interference is in- dicated in either condition. A gumma or tuberculous process inhibiting the activities of the pancreas may be differentiated from a carcinomatous growth by the fact that no con- ditions other than carcinomatous disturb the concentrations of the sulphur components of the urine. Intestinal Tract. — For diagnosis of neo- plasm of the intestinal tract we may depend to a limited degree upon the presence of pathological constituents in the feces. If the process is obstructional, chronic constipation will be the result. This constipation, how- ever, may be relieved by enemas or cathartics. It will be found that the feces, principally those following enemas or cathartics, contain occult blood. The presence of blood cannot be indicated microscopically unless the neo- plasm is in the rectum or sigmoid flexure. 88 CANCER For the detection of blood from a neoplasm higher up in the intestinal tract, we must de- pend on chemical means. The feces will be found also to contain considerable quantities of mucus and necrotic epithelial cells. It is in the localization of tumors of the small or large intestine that the X-ray is of the greatest value, and for the diagnosis of tumors of this region we must depend more upon the X-ray findings and the general effect of the growth upon the physical condition of the patient and the composition of the urine and the blood, rather than upon the composition of the feces. The sulphur partition in these cases is of value. A very common affection which shows tendencies toward malignant formation is "Smoker's Patch," or leucoplakia of the tongue. It appears as a small circumscribed white patch upon the tip or margin of the tongue and is most commonly seen in exces- sive smokers or in individuals giving a syph- ilitic history. In smokers its origin is most probably due to the irritating action of ob- noxious gases upon the epithelium of the tongue. If untreated it develops malignant characteristics that form metastases in the walls of the pharynx. The only satisfactory STOMACH 89 procedure for the relief of this condition is the complete destruction with the cautery. In the development of neoplasm from leuco- plakia or other pre-cancerous conditions we must recognize a predisposing cause, and whether the exciting cause be bacillary infec- tion, trauma, or chronic inflammation, we cannot say. However, the pathologist cannot too strongly urge upon the surgeon the neces- sity of a complete destruction of a leucoplakia as a predisposing lesion of carcinomatous de- velopment. {Note, — The normal amount of neutral sulpho-cyanate has never been determined.) CHAPTER IV Differential Diagnosis between Epithe- lioma, Syphilis, and Diseases of the Skin In a work of this character it hardly seems advisable to devote a great deal of space to dwelling on the somewhat minor points of difference between epithelioma in its various forms and syphilis and certain diseases of the skin. Although those experienced know that again and again mistakes in diagnosis occur often, many an individual has been, and is being, operated on for cancer who is really suffering from some of the protean forms of syphilis. In our experience (based to a con- siderable extent upon observations made in homes for incurables) we find syphilis mis- taken for carcinoma a hundred times more frequently than we find carcinoma mistaken for syphilis. As stated above, it seems to us more fitting to devote space to a general consideration of the means at our disposal for making positive what diseases exist, than to dwell much on all 90 DIFFERENTIAL DIAGNOSIS 9 1 the clinical points that may present themselves to the eye alone. These latter are more care- fully considered in some of the works on Dis- eases of the Skin, and are often graphically portrayed by means of color plates. The Wassermann reaction is not always a safe guide, because it is very often absent in old syphilitic cases. When found to be present, its diagnostic value naturally has great weight. In many cases, particularly those of suspected gumma, it is necessary to try very thoroughly, for at least a month, an intensive anti-syph- ilitic treatment and to observe its effects be- fore the diagnosis between it and epithelioma can be clearly made out. It is probably wiser in such cases to resort at first to mercury in some form and the iodides, for this purpose, than to salvarsan. It may be well to note here some clinical observations which we have made. These observations are not particu- larly new, but it has been surprising to notice in how many cases proper precautions have not been taken to clear up doubts which might exist as to the nature of a lesion being syph- ilitic or carcinomatous, through the careful carrying out of simple therapeutic tests. Iodide of potash, the administration of which it is well known has such an effect in causing 92 CANCER the diminution of a syphilitic gumma when the system is thoroughly saturated with it, should be administered on an empty stomach, instead of after meals, as is so often done, when it has a tendency to form the iodide of starch. Mistakes often occur in large hospitals in the proper and systematic medication of pa- tients, often so extremely important as an aid to diagnosis in the above-mentioned condi- tions, unless great care is exercised on the part of the house staff and attending physicians. Mixed treatment, containing iodide of pot- ash as it does, should also be administered when the stomach is empty; and a very thor- ough course of mercury and the iodides, of months' duration, should be instituted, and the effect carefully watched (both constitu- tional and local) in all doubtful cases. When, after this therapeutic test, no change has been observed in the appearance of a doubtful lesion, the results of this test should not be considered infallible, but should be followed by the administration, at least twice, of old salvarsan when possible to obtain it. We have found "Smoker's Patch," when due to syphilis, and gumma of the corpora caver- nosa, to be the most difficult conditions to yield DIFFERENTIAL DIAGNOSIS 93 to anti-syphilitic treatment, and thereby in a doubtful case enable us to establish a definite diagnosis. It hardly seems necessary to remark that in doubtful lesions too much reliance should not be placed upon the results of a history of therapeutic tests previously given by the in- dividual having such lesions. The effect of hypodermic mercurial medications has not the same diagnostic value as the procedures men- tioned above. Seborrhcea and epithelioma may sometimes be easily mistaken. It should be remembered that almost all forms of cancer of the skin commence with lentil-shaped papules under the skin before the breaking down of the tis- sue occurs. Chancre, herpes, eczema, and innocent erosions may be mistaken for epi- thelioma. It should also be borne in mind that while an epithelioma may develop through the breaking down of near-by mul- tiple islets, syphilitic growths have a tendency to be more multiple. This character, too, tends to distinguish it from eczema, occasion- ally there being some resemblance between the two, particularly when they occur on the face. The border of epithelioma is more sharply defined, and there is less infiltration. The 94 CANCER diagnosis of lupus can be helped by the his- tory, the age of the patient, and the tendency toward multiplication in lupus, together with the slow growth of the latter, and the fact that it has no tendency to cause constitutional im- pairment. Condylomatous warts and allied conditions may sometimes simulate epitheli- oma, and to distinguish them from these, and any of the conditions mentioned above which may simulate them, when practical, a speci- men should be obtained, and the results of the microscopical examination by a good pathol- ogist noted. The value of obtaining a careful history we wish to call attention to again, particu- larly as regards the question of heredity, which is often overlooked. It is referred to again in this work; the value of the sulphur findings in the blood and the urine are also referred to, as is the benefit to be obtained from skilful examination by X-ray pictures. The use of some or all of these latter methods helps wonderfully in doubtful cases, both in the diagnosis as well as in the prognosis, and in furnishing indications for treatment. Some of the above methods are just coming into general use, and one or two of them have practically never been tried before. CHAPTER V Diagnosis by X-Ray and Cystoscope Now that examination plates by the Roent- gen ray are being made more and more fre- quently, as they should be — not only as a diagnostic measure to show conditions affect- ing the bones, but as an aid in diagnosing any diseases of the heart, lungs, pleura, abdominal organs, and urinary system — their use has not only been of great aid in the diagnosis of any given case, but is tending to alter to a great degree our conception of the nature of the disease. This is true of malignant diseases more than any other. The surgeon is no longer in the position concerning such opera- tions as, e. g.^ cancer of the breast, that he was only a very few years ago before the exami- nation of the chest by the Roentgen ray be- came such a matter of routine. Naturally the conditions shown in the plates, such as the presence or absence of enlargement of the glands at the base of the lungs, single or mul- tiple, indications of tumors in the pleura, 95 96 CANCER mediastinum or esophagus, probably above all, peri-bronchial thickening, together with other diagnostic evidence, among which may be mentioned the amount of unoxidized sul- phur in the urine, have in a given case an effect in modifying the decision as to whether an operation is to be performed or not, also the character, and above all the prognosis in any surgical measure undertaken. In the in- terpretation of any plates it is hardly neces- sary to insist that the most careful considera- tion must be given to the proper interpretation of the shadows, and the testimony furnished through their use should be considered only in connection with the testimony furnished by other diagnostic factors in any given case. Naturally the co-operation of the attending surgeon and the radiographer is most impor- tant. This is particularly true in plates in which the shadows are as distinct as those of the bones, for, aside from trauma, so many other conditions may affect the bones, either the periosteum, the surface, or their centers, that mistakes may very easily occur. In our own work we have found that the appearance of dead bone shown on a plate, without other factors to account for its presence, is very in- dicative of being secondary to some constitu- X-RAY AND CYSTOSCOPE 97 tional disease, of which the primary focus or foci is in some other organ of the body, and which it is often extremely difficult to locate. To illustrate further, we have noticed hyper- nephroma of the kidney so small as not to cause enlargement of that organ, cause necrosis in the pelvic bones and sternum, without giving rise to indications of kidney disturbance. Syphilitic and malignant diseases of the bone are often difficult to diagnosticate from one another. Generally speaking, syphilitic growths of the bone are apt to be smaller, more nodular and numerous than malignant growths. Malignant growths of the bone are more apt to be secondary to a primary focus in some other portion of the body. Sarcoma causes more of an expansion of the bone than cancer. The age of the patient and other fac- tors often aid in the diagnosis. Sarcoma oc- curs more often in the periosteum or endos- teum than cancer. In the lung, primary can- cerous growths are rare. The shadows given by them are not always clear; they may be taken for aneurism. They are, however, oc- casionally met with both in the lobes and in the hilus. Those in the lobes generally give a shadow fairly clear, with a line of demar- 98 CANCER cation. They can be differentiated from pneumonia by the clinical history. They give a more definite outline than tuberculosis, and there is less apt to be evidence of involvement of the lung. When they occur in the hilus they are apt to confine themselves also to a lobe. Secondary cancers are found in a nodular form, and a diffuse form as well. Neoplastic nodules can be easily made out by the plates and differentiated from tuber- culosis, as they give no evidence by the stethoscope, and are quite characteristic. In diffuse form they are apt to occur at the bot- tom of the lung, and either cause an extension into the pleura or, on a plate, present an appearance of an epanchement pleuritique. If confined to the lung alone, these diffused secondary growths generally give no symp- toms on auscultation, if the pleura is not in- volved; but very often these cases are mixed up with a true involvement of the pleura. One factor also to be considered here is the negative value of these plates when the pic- tures are carefully taken by a competent radiographer. The mediastinum is clear, the pleura casts no shadows, and no nodules can be made out around the bronchi, which is good evidence that metastases have not as yet X-RAY AND CYSTOSCOPE 99 taken place. It should be noted that these nodules are small, and when the mediastinum is affected it is difficult to have the discern- ible shadows appear. The small nodules around the bronchi are easier to be made out, as is also the thickening of the pleura, which casts a denser shadow than when due to sim- ple pleuritic effusion of liquid, although it should be remembered that the cancerous in- vasion of the pleura in itself may give rise to association with effusion. Malignant growths of the esophagus, if of any size, after the administration of bismuth, are shown clearly on a plate. Radiography of the esophagus is too often overlooked, and malignant growths are frequently not diag- nosed by this measure until they have existed for a considerable time and become of quite a large size. It is rather beyond the plan of this volume to give more than a general outline of the technique necessary to bring out all the diag- nostic points that may be found in connection with the examinations of the stomach by radiography; reference is made to the last edition of Knox's "Radiography, X-Ray Therapeutics and Radium Therapy," pub- lished by Macmillan, as to the details of such lOO CANCER procedures as the administration of the opaque meal, bismuth, the position of the patient for examination, and interpretation of the shad- ows found. He states, quoting Holzknecht, that a simple ulcer of the stomach is rarely seen, although it may be suspected from the absence of shadows, indicating the passage of food through the pylorus. In malignant dis- ease involving the lesser curvature and spread- ing through the pylorus, the latter point is more or less fixed and held higher up than usual; food may be seen passing through the stricture; a sharp and persistent angle or irregularity in the pyloric region is generally indicative of malignant stricture; finally, a shadow of the growth may at times be seen on the radiographs. Malignant diseases may occur anywhere in the stomach. It sometimes shows on the plate by giving a ragged or irregular shadow, ir- regularity being due to the projection of the growth into the bismuth food; generally also a characteristic picture of stasis is presented. The abnormal conditions of both the small and large intestines following the bismuth meal can either be differentiated by, or else valuable testimony obtained from, the X-ray examinations. Most abnormal conditions of X-RAY AND CYSTOSCOPE lOI the intestines present a picture of stasis, to a more or less marked degree. Kinks may be occasionally made out by this measure, and as regards the duodenum, sometimes an ulcer, if deep, can be differentiated. Examination of the urinary tract may be performed by means of the X-ray pictures alone, through the use of the X-ray in con- nection with a metallic ureteral catheter, or following an injection of some salts of silver or thorium into the pelvis of the kidney, and rarely by an injection of some bismuth salts into the bladder. Just here it is only desired to mention the value of the X-ray for diagnostic purposes when used in showing tumors of these organs. When used alone, without the other aids just mentioned, it is doubtful if a positive diag- nosis of tumor of the kidney can be made by the use of the Roentgen ray unaided. In skilful hands, however, a shadow can be pre- sented which will demonstrate if any enlarge- ment of the kidney exists, while the density of the shadow given may at times aid in render- ing positive a diagnosis of tumor. Where examinations of the urinary tract are to be made, great care should be used to see that the intestines are thoroughly emptied I02 CANCER of their contents before the picture is taken, so that intestinal gases may not give rise to shadows; and where one kidney is examined, a picture of the other one should always be taken. The value of the cystoscope as a method of diagnosing malignant growth is naturally confined to those growths occurring in or associated with the bladder. Through the use of the cystoscope, where it is suspected that a malignant growth of the kidney exists, not infrequently the ureteral catheter can be passed through the ureter to the kidney, and through that enough solution of thorium, col- largol, or argyrol introduced, and an X-ray picture taken. The plate will show the shape of the pelvis and the kidney, and in that way may, in connection with other indications, give a fairly correct view as to whether a tu- mor of the kidney exists or not. The inability to pass the ureteral catheter in skilled hands indicates the closing of the ureter, and if a waxed tip ureteral bougie, or some other form of metal ureteral bougie, fails to indicate the presence of stone, testimony is furnished that tends to strengthen the diagnosis of some form of tumor. Very frequently, where a suspected growth exists in the kidney or ureter, it is X-RAY AND CYSTOSCOPE 1 03 better to do an exploratory operation than to run the risk of misleading diagnosis or of irritation of the pelvis of the kidney through the passage of the ureteral catheter. Con- cerning this subject, reference is made to Greene and Brooks' ^'Urinary Disease and Diseases of the Kidney," 4th edition (W. B. Saunders Co., 1917), or to Braasch's ^'Pyelog- raphy" (W. B. Saunders, 1917). It is in the bladder, very naturally, that the cystoscope is of such value in demonstrat- ing a growth. Unfortunately, many of these tumors of the bladder are associated v^ith a large prostate, so that the cystoscope cannot be passed. When it can be, an exploring cystoscope in the hands of any one that is skilled in its manipulation will, under ordi- nary circumstances, give a fairly clear picture of any abnormal lesion on the bladder walls. Just here, however, it is necessary once more to return to the consideration of the re- semblance between various forms of syph- ilitic tumors, or ulcerations of the bladder, and other ulcerations or growths, either ma- lignant or benign. Syphilis of the bladder was never recognized as a definite entity until the cystoscope came into common use. Some of us had recognized and written about syph- I04 CANCER ilis as affecting the bladder, particularly as a cause of contracted bladder, from clinical observation alone. (See reference in earlier editions of Greene and Brooks, ut supra.) But even now these conditions are being classified, and very little has been written concerning them in English. Syphilis attacks the bladder, somewhat generally speaking, in three different forms. In its earlier stages it attacks the bladder, causing numerous small ulcerations, somewhat resembling those of mucous patches on the tongue and mouth. In the later stages the ulcerations are smaller in number, but are apt to be deeper and of a polycystic character; and in its still later stage it gives rise to gumma of the bladder. These gummata of the bladder have a charac- teristic appearance, and, having once been seen, are more easily recognized than de- scribed. They are very well illustrated in the colored plates of an article by G. Gayet and E. Favre, Journal de Neurologic^ July, 1914, and have been redrawn in black and white and published in the 4th edition of Greene and Brooks {ut supra). They sometimes, in a rough way, resemble a bunch of grapes, also sessile tumors or pediculated tumors, be- ing papillomatous in shape. The later ulcer- X-RAY AND CYSTOSCOPE I05 ations of syphilis of the bladder may be mistaken for tuberculosis of the bladder when viewed under the cystoscope, and probably often have been so mistaken. Gummata of the bladder undoubtedly have been and are being mistaken either for malignant growth of the bladder or for benign bladder papillo- mata; and in all probability, in many of the cases that have been recorded as cures follow- ing operations for tumor of the bladder, these tumors have been gummata, and neither ma- lignant nor simple papillomata. These syph- ilitic lesions have more of a tendency to grow upward and less of a tendency to infiltrate the bladder wall than malignant growths. From either malignant growths or from benign papillomata they are at times extremely diffi- cult to differentiate, and when possible a care- ful microscopical examination of any bladder growths should be made. Probably where a syphilitic ulceration of the bladder has been marked, its after-effect is to cause connective tissue in the bladder wall and give rise to contracted bladder. It may also be stated that many cases of late syphilis of the nervous system, such as locomotor ataxia, have syph- ilis of the bladder as well, instead of having their bladder symptoms entirely due to some I06 CANCER sclerotic or other condition in the spinal cord; syphilis of the bladder may coexist with them. In these cases mild anti-syphilitic treatment is of benefit for the bladder symptoms, in addition to whatever local treatment may be given them. In all doubtful cases of bladder lesion portrayed by the cystoscope, all other diagnostic factors possible to obtain should be collected and analyzed before a diag- nosis of the presence or absence of malignant growth of the bladder is made. CHAPTER VI General Consideration of the Condition OF Blood, Hair, Nails, and Saliva In addition to what has previously been mentioned in this volume concerning the vari- ous methods to be considered in the diagnosis of malignant growths, there are a few others which we believe will, in the not far-distant future, be taken into account as diagnostic factors, and concerning which at the present time comparatively little is known or has been written. They are of enough importance at least to be mentioned. Concerning the blood in general, as regards its chemical analysis, there is still a great deal of work to be done to establish definitely the amount of the chemical constituents in nor- mal blood, and also in the discovery of new tests which will demonstrate the amount pres- ent of some of its constituents, where only small quantities of blood can be obtained for examination. The work done by us apparently demon- 107 Io8 CANCER strates what the normal amount of sulphur is in the blood, about 36 milligrams to 100 c.c. of blood. But still further work needs to be done to demonstrate the absolute cor- rectness of these figures, that is, as to whether this increase of sulphur in the blood is found in carcinoma alone or not, as our work would seem to show, and further work in the chem- istry of the blood is needed to demonstrate the normal amount of potash and some other substances. It would appear that, within the next few years, judging from the rapid ad- vance made recently in discovering new meth- ods for estimating the chemical constituents of the blood, the chemist will be more and more frequently called on to examine the chemical blood constituents in given cases. It would also appear that these examinations will be made with increasing ease and be of more and more frequent aid in the diagnosis of many diseased conditions. In addition to the infor- mation that can be obtained from the blood at the present time, and what may be expected from its chemical analysis in the near future, there are other factors, such as the observa- tion of the hair, condition of the nails, and chemical examination of the saliva, which may render at times valuable information. BLOOD, HAIR, NAILS, ETC. 109 We are indebted to the observations of an ardent believer and scientific worker on the subject of sulphur changes in the urine and sulphur metabolism in the system in cancer generally, Dr. F. von Oefele, for the obser- vation that ^^Bald-headed men never have cancer^'' ('^Quantitative Urine Analysis, with Special Reference to Carcinoma Metabol- ism," Trans. Ger, Med. Soc.^ March 4, 1912). Naturally this statement can only be taken semi-seriously, for the loss of hair from the scalp can be due to many different causes. But in a general way there is probably some truth in the statement, for it seems to be true that sulphur plays a very important part in the development of the hair, and that the lack of sulphur also plays a part in causing its loss. Sulphur changes are, possibly, the cause of the falling out of the hair after an acute in- fectious disease like typhoid. Sulphur which would naturally tend to nourish the hair and the scalp is used up in the intestinal canal in overcoming the products of decomposi- tion caused by the activity of the infected condition appearing there. With the increase of sulphur in the system, such as appears to exist in individuals with malignant growths, it might be expected that the hair would re- no CANCER ceive its proper amount of nourishment as far as sulphur is concerned; and, the other factors being normal, bald-headed people would be less subject to malignant growths, so far as the lack of hair is an indication of a lack of an increase of sulphur in the system. The condition of the nails may not, and probably do not, demonstrate anything of diagnostic value of a malignant growth. The probabilities are that the sulphur element in the development of the nails is comparatively a minor factor. Split nails may show a lack of potash, which is supposed to be increased in the case in most individuals suffering from malignant disease, and in that way be an indi- cation that no such diseased condition exists. So far as our own observations go, it is so limited in this respect as to have but little value. It is only mentioned, however, as one of the factors that should be borne in mind, observed, and recorded in history taking. The saliva^ concerning the chemical analysis of which comparatively little work has ever been done, may, through its examination, occa- sionally furnish valuable data. Sulphur exists in it in the form of sulphur cyanate. When the normal amount is finally ascertained and some easy test devised to determine the excess BLOOD, HAIR, NAILS, ETC. Ill or diminution, it may furnish an easy method not only of aiding in the diagnosis as to whether or not some departure from ordinary tissue metamorphosis exists, but also be a guide in showing the effects on such metamor- phosis of any remedial measures which may be undertaken. These examinations should be of impor- tant value in connection with such conditions as ''Smoker's Patch," the origin of which is sometimes very difficult to determine. PART IV TREATMENT OF CANCER CHAPTER I Basis of All Successful Treatment to be Found in Measures Which Tend to Increase Tissue Metamorphosis Success in the treatment of cancer, like that of many other diseases, will depend to a great extent on the diagnosis ; on the correctness of this, and the recognition of cancer in its earlier stage, the principles of treatment are founded. It is more than possible, it is prob- able, that through the recognition of a pre- cancerous state, if such a term can justifiably be used, the adoption of proper methods, both hygienic and medicinal, to increase tissue metamorphosis, will often prevent the disease from becoming constitutional, prolong the life of the individual, diminish suffering, and what may be of even greater importance, limit the activity of the predilection to the disease 112 GENERAL TREATMENT II3 which may be transmitted to others. Individ- uals in whose family history may be traced a predilection for cancer, in whom the neutral sulphur constituent of the blood and the urine are found to be above the normal, who show a tendency towards a slow repair following injury or accident, and particularly those whose mucous membranes are unusually easily subject to excoration, or such conditions as relapsing herpes from slight irritation, belong to this class. The above conditions, or similar ones, are considered of sufficient importance to be re- ferred to more than once in other portions of this book. Concerning the medicinal treat- ment in general to be adopted, it is difficult to separate the preparations to be used into clearly defined classes. Somewhat generally speaking, it may be stated that for internal administration one class consists of prepara- tions which can probably be considered as tonics. And even the action of these is not at the present time clearly and distinctly un- derstood, but they probably act on the hema- tin in the blood, and through increasing the hematin in the blood increase the resistant power in the cell. To this class belong ar- senic, iron, manganese, and vanadium. An- 114 CANCER other class of agents, such as selenium and tellurium, act as diuretics, as oxidizers, or else in some way with which we are not en- tirely familiar, enter into combination with the sulphur in the cell in such a form as to tend to stop increased cancer-cell prolifera- tion. If they act as oxidizers, it might be sur- mised that the neutral sulphur would be changed to sulphates, and that an increase in the latter and a diminution of the former would be found to follow their administra- tion. The third class contains such constituents as condurango, echinacea and the like, whose action has so far been undetermined, but in advising the use of which our experience cor- roborates that of some others as to the bene- ficial results following their administration, which is at the present time (at least to a con- siderable extent) empirical. The above refers to preparations for inter- nal administration. To a considerable extent the same preparations not infrequently in a different chemical combination will be found to be useful for external application for ul- cerations associated with malignant growths, but which are not malignant growths them- selves. Reference is here made to the state- GENERAL TREATMENT I15 ment in one of the earlier chapters that the ulceration is not the disease, but is merely one of its manifestations, and it is also necessary to keep the surrounding tissue in as aseptic a state as possible, so as to prevent further in- fection. This is in addition to whatever di- rect application over ulcerated surfaces may be made of a stimulating nature, such as radium. X-ray, arsenous acid paste, or any other cauterizing agencies; applications to certain ulcerations are also necessary to pre- vent the odor or to relieve pain. It has been found by us, that for an external application that will relieve the odor, where skin sur- faces are ulcerated, tend to stop the spread of the ulceration and relieve the pain, a modi- fication of Dakin's solution is the most use- ful, made according to our formula given later on, to which has been added a slight amount of selenium or tellurium. This, we consider, is the most useful, although the ab- solutely ideal preparations for this purpose have not as yet been found, and probably never will be, as there are too many different op- posing factors to be controlled to make any one preparation fulfil all the indications. Ointments which contain vanadium and selenium in an unirritating base are sometimes Il6 CANCER useful either in protecting surfaces adjacent to the ulcerated area, or through their effect as an inunction in administering selenium to the system. There are several preparations on the market for this purpose, but care should be observed when using them not to let them touch the ulcerated surfaces directly, as they cause irritation. Concerning deodorizers, the difficulty met with in solutions as deodorizers is, that a true deodorizer is a difficult thing to discover. Chlorine in some form which acts as a disguiser of any unpleasant odor is good, but is in almost all forms apt to be irri- tating. The preparation which we present further on, with a definite statement as to its manufacture, is the least irritating and the most useful that we have so far been able to obtain. Our experience with some of the preparations for external use that will relieve pain, such as orthoform, although recom- mended by many, has been disappointing. Aristol, lead and opium wash, and many un- irritating ointments, all have their place ac- cording to the needed requirements of the individuals. We prefer to mention throughout this work the substances which we ourselves have found to be the most beneficial. And at the GENERAL TREATMENT II7 risk of repetition it may be stated that the Dakin's solution made according to the method which we give, and with the addi- tion which we recommend, is not only of great aid from its constituents, but from the method of applying it through the tubes, a constantly moist application to the ulcerated surfaces is insured. Life in the open air for these poor sufferers is very beneficial. In this part of the world they are always better in summer than in win- ter. It has never been thoroughly tried out so far as we are aware, but it would not be surprising if in days to come it was found that life in the open air would be of almost as much benefit to individuals suffering from cancer where the diagnosis has been made of its existence in the earlier stages^ as previously referred to, as it is in cases of tuberculosis. One of us was exceedingly surprised and pleased to observe in a visit made to the home for incurables at Hawthorne, N. Y., some few months ago, the wonderful vitality exhibited by the patients in this home for incurable can- cer. Several patients there with cancer of the stomach had been inmates from several months to several years, in whom, while the diseased condition was not cured, it had ap- Il8 CANCER parently been arrested. In that institution, outside of the comfortable hygienic surround- ings, good nursing, and abundant food sup- ply, the improvement could only be attributed to the abundance of fresh country air, the in- stitution being situated on a hill a few hun- dred feet above the sea level. The probabilities are that these cases do better under the same climatic conditions as tuberculosis patients do. But so far as we are aware, statistics are lacking to show the best climatic conditions for these people. The same rules should probably apply as are found the best in sanitariums for sufferers from tuberculosis. They should keep in the open air practically all the time, with an abundant food supply, and be provided with some oc- cupation so far as the given case permits. If such conditions as frequent retardation of the malignant growth exists, as we found in the institution mentioned above, which is consid- ered a home for incurables, and in which, so far as we are able to observe, no medicinal treatment beyond ordinary palliative meas- ures was administered, what might not be hoped for in similar institutions if the diag- nosis was made early, and a systematic method of medicinal treatment, in addition, carried GENERAL TREATMENT II9 out? Unfortunately, the death rate in homes for incurable cancer in the large cities is ex- tremely high. The main reason for this is that patients are received there practically moribund, and in such a state that their sys- tem has been thoroughly undermined by a general carcinomatosis, with not only one but so many infected processes at work that ordi- narily anything beyond the relief of pain is practically impossible. Even in such insti- tutions, however, more attention to details in the carrying out of some properly formulated and well-planned remedial measures will lower the death rate, and very materially in- crease the number of patients who could be discharged if not cured, at any rate with the diseased condition practically arrested. At present this rarely happens. The food supply is one concerning which there has been considerable discussion ; dietary sheets have been compiled according to the point of view concerning the cause of cancer which is held by the attendant. It is hardly our desire to go into a discussion of the vari- ous regimens which have been suggested. Up to the present time we are of the opinion that under ordinary circumstances a mixed diet of well-cooked food is preferable, modi- 120 CANCER fied necessarily according to circumstances surrounding any given case. It has been sug- gested by some, very cleverly and perhaps wisely, that an attempt should be made to use food as free as possible from sulphur. An in- teresting article has been written by Dr. Kess- ler concerning this sulphur-free diet ("Diet in Carcinoma," N. Y. Med. Jour., 1912). If our view of the sulphur metabolism is the correct one, the condition of the individual will neither be improved nor made worse by withholding the ordinary amount of sulphur constituents from the system. It is hardly necessary to speak about bath- ing, more than to say that it is an advantage in keeping the skin in as good a condition as possible, and above all of value as the cir- cumstances surrounding any given case will permit of inducing perspiration as a method of cleaning the inside of the skin, relieving the kidneys, and improving the general con- dition. In fact, some medicinal preparations used for malignant growth have probably been of benefit through their action in stim- ulating perspiration. CHAPTER II Vanadium and Arsenic. Iron and Man- ganese. CONDURANGO, AND OTHER BIT- TER Tonics Having found (as stated in previous chap- ters) that all oxidizing agents properly ap- plied are of benefit in cancer, v^e state, as sim- ply as possible, the manner of using the above- mentioned remedies which we have found most useful, believing that in so doing we avoid going beyond the limitations of this work and invading the field of polyphar- macy. It is claimed that vanadium is more power- ful than arsenic, while its toxic effects are about one-tenth less. Solutions of soluble salts in strengths of from 1-20,000 to 1-50,000 make very good antiseptics. Our experience with vanadium is limited, but sufficient to make us consider it worthy of further inves- tigation; it may prove to be a much better tonic than arsenic. It can also be combined 121 122 CANCER with selenium, to make salts of the two ele- ments, Vanadium selenides, of which there may be several, di-, tri-, tetra-, penta-sele- nides, V2Se2, V2Se3, V2Se4, V2Se5. These combinations are very insoluble, and therefore for internal use they are unsatisfactory. When, however, any of these vanadium sele- nides are combined with either potassium or sodium they form potassium selenovanadate, or sodium selenovanadate, both of which are soluble. Solutions of these have been given in doses of from one to two milligrams three times daily, and it is reported that satisfactory re- sults have been obtained from their use. For external use, preparations of vanadium and selenium, the vanadium tri- or penta- selenide, in the form of 3 per cent to 5 per cent ointment, have proven satisfactory. The base recommended is a combination of eu- cerine and lanoline. Within the last few years several prepara- tions of vanadium by different manufacturers either in this country or abroad have ap- peared. So far they have been used to a very limited extent. Within the last four or five years they have received some recognition either alone or combined with other elements, VANADIUM, ARSENIC, ETC. 1 23 as a method of retarding growths. Their use has been recommended for internal adminis- tration or for external application for the same purpose either alone or combined with selenium, or with an ointment base as men- tioned above. When used combined with selenium externally it has been with the idea of administering selenium through inunction for its constitutional efifects, and with the idea of making the action of the former less de- pressing. The exact action of vanadium has not yet been studied carefully enough to be understood, but it probably has a constitu- tional efiPect resembling that of arsenic more closely than any other element; acting as a tonic and as an antiseptic in some way, toning up the cell by the above measures and making the tissues become more resistant to bacterial invasion. It is never administered in a metal- lic state internally, but always as a soluble salt, and generally in combination with some other element or acid radical. When administered alone it is generally given in the form of vanadic acid or vanadium oxychloride solu- tion. We have not had any experience with this element administered alone, but we have observed its efifects in several cases when given in one to two milligram doses three times a 124 CANCER day, when administered as potassium seleno- vanadate. This solution is probably one which is somewhat unstable, and not as easy to obtain as colloidal selenium, but in the few cases in which we have tried it the results have apparently been as satisfactory as could be expected, and no depressing after-efifects have been noticed to follow its administra- tion. Vanadium oxychloride, vanadium sul- phate, or any soluble salt has been used for antiseptic solution in the strength of 1-20,000 to 1-50,000. Arsenic, since its discovery, has justified its reputation as a useful remedy for diseases of the skin, and also as an alternative oxidizing tonic for the system when administered in- ternally, and probably in some form or other, either externally, internally, hypodermically, or intravenously, is employed more than any other strictly medicinal agent for cancer. In our experience with it, which, while some- what limited, has been to a great extent in far advanced cases, w^e have not found it as useful as the proper preparation of selenium, vanadium, and to some extent tellurium. But aside from these it seems about as useful as, and safer than, some of the other more re- VANADIUM, ARSENIC, ETC. 1 25 cently discovered methods for the treatment of this disease. It should be noted that as an oxidizing agent arsenic and vanadium are concerned principally with carbon, and hydrogen, while oxygen is the compound with which selen- ium and tellurium are most intimately asso- ciated. Again, at the risk of indulging in repeti- tion, we wish to call attention to the fact that there is a wonderful resemblance in cases of old syphilis and of cancer; in some form they seem to be cousins, and while arsenic gives very brilliant results when administered in- ternally, or especially intravenously in the form of salvarsan, very great care indeed should be used to be sure that a proper differ- entiation has been made between these two diseases. Arsenic in the form of salvarsan, neosalvarsan, or some of its substitutes, should, when practicable, be administered in two large doses at intervals of a week, and its effect watched in all doubtful cases, and in those in which the slightest uncertainty ex- ists, even if a month's previous treatment by means of mercury and the iodides has caused no effect. Salvarsan and neosalvarsan have been used as remedies for undoubted carcin- 126 CANCER oma itself, with apparently occasional bene- fit, and recently they have been recommended by such an exhaustive writer on the subject as Roncali (Trattato di Neoplasmi Maligni, Torino, 1916). He finds its administration more efficacious in the connective-tissue than in the epithelium growth. In the administration of arsenic internally as an oxidizing tonic, ordinarily we prescribe a fifth of a grain of arsenous acid in the form of a freshly made pill dusted over with black pepper, three or more times a day; this is the ^Til. Asiatica" of the old pharmacopoeias. We have not infrequently found arsenous acid paste of great value as an external application to epithelioma of the skin, naturally not the mucous membranes ; we have sometimes found this apparently of more benefit than excision, particularly in places like the angle of the eye, where excision was a difficult and awk- ward operation to perform, and it has also been of great use in cases of epithelioma after the application of radium and the X-ray had proved inefficient. We use the paste, of which the following is the formula: VANADIUM, ARSENIC, ETC. 1 27 Arsenic Paste Acid arsenous, one-half dram. Amylum, \ Powdered alum, v of each, two drams Glycerine, ) Distilled water, one-half dram. Mix. This is approximately 7 per cent; we also use it in a strength of 10 per cent and 15 per cent. If this paste becomes too hard for ap- plication it should be warmed, before using, in a warm bath; a little hot water may also be added. It is sometimes difficult to tell which strength is the best adapted for the in- dividual until two or three have been tried out. The application should be of a strength sufficient to cause reaction, such as swelling, reddening, and possibly some increase in dis- charge, for from one to two weeks after its application, during which time some simple ointment like cold cream should be applied, and when the reaction has entirely subsided another application should be made of the same strength or stronger, as is held to be the correct view for the particular case. This paste should simply be painted over the sur- face of the ulcerated area, not beyond it, 128 CANCER lightly but thoroughly, with a cotton or wooden applicator, once. The reaction will start immediately. But again attention must be called to the fact that where the external applications of arsenous acid paste seem to be of great benefit it is well to combine with them the internal administration of selenium and vanadium or some other of the oxidizing elements of like nature already mentioned. Where it is not practicable to obtain these in their proper form arsenic should also be ad- ministered internally as well as externally, and with the proper periods of rest, so as to avoid its cumulative effects during the re- maining lifetime of the patient. Iron, the well-known oxidizer when admin- istered in such form as not to irritate, is of great value in cases of carcinoma, in associa- tion with whatever other methods may be tried, except possibly some of the newer oxi- dizing agents mentioned, which apparently do better when administered by themselves. Naturally enough, in cases far advanced, it has been noted by others (and written about) that a profound anemia is apt to exist with a marked carcinomatosis; in this condition, with the exception mentioned above, like other oxidizing substances, iron is indicated. VANADIUM, ARSENIC, ETC. 1 29 in addition to that even where the blood- count or hemoglobin are not materially re- duced. It is well to use it in whatever form is found to be the least irritating; as, tartrate of iron and potassium, or as a peptonate, or it can be combined with manganese, which deservedly enjoys a reputation as an oxidizing agent. This may be administered with iron, or separately, often, and in as large a dose as can be borne without causing irritation, and for long periods of time. The idea being that all of the above, together with the proper hygienic surroundings, excision, radium, X- ray, or other agents, may help to retard the growth of the cancer, even if it is not cured; so that the individual may live in compara- tive ease, and possibly die of some intercur- rent disease which is apt to cause less suffer- ing than cancer. We now come to consider a class of reme- dies concerning the therapeutic effects of which but little is known; but as a result of our observations we believe that some of them are of service; but in what way they are a benefit is a problem for the physiological chemist to work out. Since the beginning of time, apparently, herbs of various kinds have enjoyed a reputation for their beneficial ef- 130 CANCER fects on cancer. This has been particularly true among natives in inaccessible regions, where medical aid has been hard to obtain. It is interesting to note that they often have a remedy for snake-bite and for cancer. Gen- erally, they are found to be preparations which induce perspiration. Dried violet flowers, in our observation, seems to have been the favorite in this respect; made into a tea and drunk freely, it certainly seems a useful remedy to induce perspiration, and has been recommended by some scientific workers as useful for certain forms of skin disease. The tea made from hemlock buds, also, has its reputation, but in this the amount of resin is considerable, and is liable to cause gastric irritation. There are some two or three bit- ter tonics which we have used that have ap- parently been of benefit, whether by increas- ing tissue metamorphosis in such a way as to help oxidize the amount of neutral sulphur apparently always present, or whether simply by stimulating the digestive organs so that they aid in assimilation of food, is beyond our knowledge. Of these, condurango occupies the first place; echinacea administered with it may or may not add to its value. We have, therefore, been in the habit of administering VANADIUM, ARSENIC, ETC. I31 to those cancer patients, where we have not been able to obtain the other oxidizers which we have found to occupy the first rank (as selenium and vanadium), the bitter tonic of which the following is the formula: Bitter Tonic Gondurango bark, Sarsaparilla root, , . 1 1 ir ^11 , / 01 each, hall ounce Columbo root, \ ' Echinacea, Boiling water, enough to make one pint. Make infusion, and filter. Dose: Half ounce in water half hour before meals. We have found it to be well borne and of apparent benefit, even by those suffering from profound general carcinomatosis; although, of course, it is not recommended in any way as a cure-all. For the skilful preparation of this, as well as the arsenous acid paste recom- mended above, we are indebted to the kind offices of our friend, Mr. Louis Protzmann, a well-known pharmaceutical chemist of this city. CHAPTER III Radium, X-ray The more the investigator carefully exam- ines the evidence furnished by the later meth- ods of the treatment of malignant growths, and separates out as far as possible from such evidence the mass of conflicting testimony, both pro and con, which must be thrown aside from the unreliability of its source (this term being used to cover irregularities in reports due to varying causes), the more forcibly is the investigator confirmed in any views held as to the constitutional character of carci- noma, and the more profound is the convic- tion that the varying lesions treated are, and can only be, local manifestations from consti- tutional disturbance. Among the later and most carefully worked out are the treatments of such lesions by radium and the X-ray, In the fourth edition of the work of Greene and Brooks, IQ17, previously referred to, the statement is made that radium has come to stay. Since its publication further experience 132 RADIUM AND X-RAY 1 33 and consideration of cases previously treated has not made it necessary to attempt to modify that statement. But like many other proce- dures, both surgical and medical, which have been heralded with considerable enthusiasm, too much has been claimed for radium on the one hand, and on the other hand scepticism has been too pronounced. Attention is called to a conscientious and scientific work recently published, "Radium Therapy and Cancer," by Henry H. Janeway, M.D., Benjamin So Barringer, M.D., and Ghoacchino Failla, E.E., A.M., published by Paul B. Hoeber, New York, 1917. Particularly to be read are the general conclusions of Dr. Janeway, page 222. Our conclusions concerning the value of the use of this element up to the present time are as follows: that radium, like other factors that can be employed, will not cure cancer. It will sometimes cure lesions caused by cancer, and by so doing retard can- cer better than any other agent that can be used. Its use seems to be of particular benefit in cancer of the mucous membranes. Our own experience in the use of this substance, either when demonstrated in our own cases or in cases which have come under our observation, has not been extensive. On the other hand, 134 CANCER it has been interesting, and has covered fairly well quite a few lesions due to cancer of va- rious types, and also such a sufficient period of time that that valuable factor has helped us in the formation of our conclusions. Very little, purposely, has been recorded in this volume regarding individual cases; but just here space will be occupied in mention- ing a few cases which demonstrate the char- acteristic effects of radium. Two of the younger men associated with us at the time were the first in this country, so far as we are aware, to try radium for carcinoma of the bladder. A few months after the radium had been applied, the application in each case having been made through a supra-pubic in- cision, the cases were reported at the New York Academy of Medicine and published ("Application of Radium in the Bladder for Carcinoma, with Report of Two Cases," F. J. Schoenenberger, M.D., and William Scha- pira, M.D., The Journal of the American Medical Association) . One of these patients died, apparently from metastasis in the kid- ney, about six months after the application of the radium, the bladder in the meantime hav- ing been apparently cured. The bladder le- sion in the second case was also apparently RADIUM AND X-RAY 1 35 cured, the man gained many pounds in weight, cystoscopic examination failed to show anything but a scar where the growth had been, and in this case part of the growth had been removed by excision for microscopi- cal examination. He continued in this con- dition for two years, at the end of which time he was lost sight of. At the end of three years he appeared in the wards of the hospital with which one of us is connected, with an exten- sive reappearance of the cancer of the blad- der, at the seat of the previous lesion, and died under our observation within a few weeks. Another interesting case was that of a woman who came under our care, for a small papillomatous growth, appearing six months after an operation for the removal of the uterus and ovaries, through the vagina. The diagnosis was confirmed by microscopi- cal examination. When a papilloma ap- peared in the vagina at the apex of the old scar the case was referred from the hospital in which she had been operated on to a home for incurables, and on account of the hemor- rhage was referred to one of us. Cauteriza- tion had no effect on this growth. The pa- tient was very thin and weak; hemoglobin 50 per cent, Wassermann negative, cachectic 136 CANCER appearanceo Finding other measures give no relief, two applications of radium emanations were made. About two weeks after the first one the growth, which was about the size of the end of the little finger, disappeared. The hemorrhages ceased, the woman lived a year, and then died, apparently from a general car- cinomatosis. It was impossible to obtain an autopsy. In this case it seems undoubted, as in the one recorded above, that the use of ra- dium prolonged life. At the present time cancer therapy by means of radium is so associated with its treatment by X-ray that the two should prob- ably be considered together. To a consid- erable extent the nature of the treatment is the same, and it is also true that a persistent search is being made with both of these meth- ods to find out more about the laws under which they work, the right dosage of both for any given case, and the safeguards to be em- ployed in their use. Radium can be made to penetrate the tis- sues deeper than the X-ray, and naturally is much more expensive to use, and more diffi- cult to obtain. Following operations for such conditions as carcinoma of the breast, one or two applications of radium may be made, fol- RADIUM AND X-RAY 1 37 lowed later on by a more diffuse and general application of the X-ray over the medias- tinum and adjacent parts. In other words, the X-ray is apparently being used more dif- fusely now than was the former custom whei/ X-ray applications were first applied. Attention is being called to the very in- genious methods of Dr. Murphy, of the Rockefeller Institute, concerning which com- paratively little has been written ("Hetero- plastic Tissue Grafting through Roentgen- Ray Lymphoid Destruction," The Journal of the American Medical Association, 1917). His method, as we understand it, consists in the application of comparatively mild doses of the X-ray upon such conditions as carcin- oma recurring in old scars following exci- sion, the strength and frequency of the appli- cation being regulated by its effect upon the lymphatics. The idea being that in mild doses its application may encourage lympho- cytosis, and through that means have an in- hibitory effect upon the growth; whereas, if the strength of the application was too severe it would be shown by the destruction of these elements, and through this measure increase the activity of the malignant processes. It can be safely stated that so far the beneficial ac- 138 CANCER tion of the X-ray in its various forms seems to be confined almost entirely to smaller le- sions, particularly those upon the skin, and that its use apparently has never been demon- strated to be of any great value for the deeper- seated lesions, like those in the mediastinal glands; but experiments in this latter direc- tion are being made, as mentioned above. If our conception of malignant growths is correct, as we believe it is, to the extent that we have expressed it, that carcinoma is a con- stitutional disease, it would not be expected, then, that X-ray therapy would have any greatly beneficial effect upon it, more than to be of considerable aid in certain of its skin manifestations. Under such limitations it would seem to us as if the method suggested by Dr. Murphy is a valuable one, and that in certain cases beneficial results might be expected to follow its administration in the manner suggested by him. Fulguration also has, we believe, a useful field (but one not yet clearly defined) in the removal of small growths either on the skin or mucous mem- branes. CHAPTER IV Excision The value of excision as a therapeutic measure in various forms of cancer is a some- what difficult one to write about, as so many perplexing questions necessarily arise in con- nection with it. Among others, is the proper amount of consideration to be given to vari- ous divergent views. The road is a long one between the views of those who believe that ''cancer can be cured without a knife" and those who advocate the removal of large areas of tissue and all lymphatic glands pos- sible to be found in the vicinity of the growth, and even go so far as to recommend such pro- cedures as female castration for carcinoma of the breast. It will be easier for those who have read the preceding chapters to understand our views, which are founded not only on our own belief in the nature of the processes to be dwelt with, previously recorded, but also on the results of our clinical observations and 139 140 CANCER experience in surgical procedures; and while to some degree they may diverge from the ex- treme views held by many, they also to a con- siderable extent tend to bring many of the divergent views into a certain amount of ac- cord. We realize that, in making the statement that the value of excision for a growth as a therapeutic measure will depend upon the circumstances surrounding each given case, we offer nothing new. But the refinements of diagnosis now at the command of the surgeon, to which we have endeavored to make some contribution on our part, enable him to un- derstand the circumstances which surround any individual case much more clearly than would have been possible a few years ago. We make the statement clearly that, in our belief, "no operation will cure cancer." On the other hand, a statement can be made with equal truth that the proper operative proce- dures will often retard its active development to such an extent that the individual's life can be prolonged for many years, so that they may die from some intercurrent disease, and that they are often our best therapeutic pro- cedure. Whatever may be its finer, primary, patho- EXCISION 141 logical, or original cause — that cancer (like syphilis or tuberculosis) is a constitutional disease, there seems to us no doubt; and oper- ations for the cure of cancer no more cure can- cer, however much they may retard it, than does the removal of a tuberculous kidney cure tuberculosis; although both may be of help to the individual. Possibly the removal of a gumma might, and probably often has, when it has been removed through a mistake in diagnosis, aided in the same way a syphilitic individual. The factors to be considered in determining the character of the operation to be performed are: (i) heredity; (2) nature of the growth ; (3) extent of the growth, particularly as de- termined by carefully taken skiographic pic- tures; (4) previous treatment; and (5) the general condition of the patient. A consideration of the above should tend to modify the decision as to the operation and its character. The above refers to operative procedures for primary and generally extensive lesions of cancer, when of more than a palliative character. The indications for these latter are often present, and naturally they fre- quently are, and should be undertaken for the \ 142 CANCER purpose, if not of prolonging life to any great extent, for the relief of hemorrhage, pain, and general discomfort. In connection with oper- ations, and basing our opinions not only on the results of our own, but that observed from the surgical work of others, we believe that the mistake more often made than any other is the neglect of the after constitutional treat- ment of patients, following whatever opera- tive procedure may have been instituted, whether with the hope of a radical cure or as a palliative measure. The details of such treatment are recorded in other chapters of this w^ork. This neglect is evidently based on a very general misconception (which how- ever, is, we believe, being gradually over- come) of the nature of the disease. That the above statement is correct will be forcibly impressed upon those observers who have been given the opportunity to carefully examine cases which come to institutions that are intended for the treatment of malignant grow^ths; and, above all, those who have ob- served condition of affairs as they exist in the various homes for incurables. Even in these latter, there is a tendency to too much laxity in careful history taking and supervision of both hygienic and medicinal remedial meas- EXCISION 143 ures. Not infrequently in them are the proper measures for diagnosis overlooked, and care- lessness used in the methods to differentiate malignant growths from the later lesions of syphilis, which could be easily benefited by constitutional measures. In such institutions suffering should be ameliorated by the proper application of every suitable remedy, both external and internal. In addition to the above, by proper laboratory, out-patient, and autopsical work, some of these places which are now used mainly as homes for the un- fortunate to die in would become, in addition, centers for scientific research, and thus aid in the discovery of new methods for the combat- ing of disease. In closing this chapter we wish again to emphasize the fact that in any given case, be- fore operating, the surgeon should be sure that he has used, if not all, at least all practicable diagnostic procedures that are at hand, among the most important of which may be again mentioned the necessity of a stereoscopic X- ray picture, and, when possible, examination of the sulphur contents of the blood and urine. CHAPTER V Selenium and Tellurium Mendeleeff has divided all the elements into groups according to their atomic weights and properties. According to this classifica- tion it appears that the properties of the ele- ments bear the same relation to one another as that manifested by the atomic weights. According to this grouping, selenium is placed in the same group with sulphur, which means that its properties, chemical and physical, are analogous to that of sulphur. In addi- tion to the chemical and physical properties of these elements, we find that their biochem- ical properties depend as well upon the grouping of Mendeleeff. In its physical forms selenium closely resembles sulphur; that is, it may assume several allotropic forms, but, however, it differs from sulphur in the fact that it is a metal. Like sulphur, it forms binary compounds, analogous to the sulphides. These compounds are called selenides. In its metallic form it forms salts, and one of the 144 SELENIUM AND TELLURIUM 1 45 most interesting compounds of this type is the sulpho-cyanate. The compound of selenium that oxidizes possesses colloidal properties and is generally referred to as colloidal selenium. The fact that selenium and sulphur belong to the same group means that selenium has the property of replacing sulphur compounds, and this fact is of extreme importance in its biological relations. Only a limited amount of work has been done upon the biochemical properties of selenium and selenium salts. They are chiefly stated as follows: If selenous salts are administered, they are excreted in the urine as such. On the contrary, if selenic salts are given, the selenium is excreted in the form of selenous compounds; this means that selenic salts have been deprived of their oxygen, and this oxygen has been utilized in oxidation processes within the body. Further, it has been observed that this oxidation by the selenic salts is confined principally to sul- phur compounds. On the other hand, arsenic and vanadium in their compounds may act as oxidizing agents, but their oxidation is con- cerned principally with carbon and hydrogen. Another interesting fact concerning the effect of selenium salts upon the organism has 146 CANCER been demonstrated by Wassermann. He ob- served that the administration of selenium salts led to an increased output of uric acid, urea, and creatinine. In confirmation of these investigations we must state that our results, obtained from the blood of a patient receiv- ing the selenium compound, has shown that the concentration of uric acid in the blood was far below normal, that is, less than .5 of a milligram to 100 c.c, and likewise the amount of urea and creatinine in the blood was abnormally low. This means that the kidneys were stimulated to increased activity. Selenium compounds likewise produce a phagocytosis, a fact of great importance therapeutically where we are dealing with an infection superimposed upon a carcinomatous condition. The most important problem presented to the chemist in the therapeutic application of selenium compounds is the elaboration of a product of selenium which is soluble, easily assimilated, and non-poisonous. Selenium it- self is not soluble, and therefore is of little value. All the salts employed by Wasser- mann were, on continued application, toxic. But later investigations have shown that it is possible to produce compounds with no SELENIUM AND TELLURIUM 1 47 toxic properties. The most commonly em- ployed compounds are potassium seleno-cya- nate. This compound is analogous to the sulpho-cyanate of potassium. However, the selenium is taking the place of the sulphur. We do not recommend the use of the seleno- cyanates, except with extraordinary caution, inasmuch as they contain the CN group, and they have been observed to have a cardiac depressant effect. If we wish to effect a com- plete oxidation, and therefore an excretion in an innocuous form of the product which we have observed in the blood, the increased sulphur and non-protein content, the most logical therapeutic agent to apply is the com- pound of selenium and vanadium with potas- sium, commonly known as potassium seleno- vanadate. In this compound the oxidation of the sulphur and nitrogen is effected by the selenium, while the oxidation of the carbon and hydrogen is brought about by the va- nadium. In addition to the fact that the selenium has the effect of a diuretic, and al- though little is known concerning the potash metabolism in carcinomatous conditions, from the results obtained it is safe to say that the administration of potash salts is apt to be followed by an improvement in the condition. 148 CANCER While the administration of the above preparation has been attended with good re- sults, when administered in the form of a solution, probably for ordinary commercial purposes, it is not as practical, and its thera- peutic properties will not be preserved for as long a period as if it is administered in the form of a tablet, of colloidal selenium, with the action of which we are also fa- miliar. It may be used in administration by mouth, by injection intravenously, and in- tramuscularly. Our results lead us to recom- mend the oral administration. During the intake of selenium salts the sulphur excretion of the patient must be carefully observed. It will be noted that an increased output of the sulphates with a corresponding decrease of the neutral sulphur closely follows the ad- ministration of selenium. The point will be reached where the intake of selenium has become so great that it is no longer fixed in the tissues or utilized in oxidation. It may then be detected in the urine in the form of the hydrogen compound. Hydrogen selenide has a very disagreeable penetrating odor, suggestive of decayed horseradish, and its presence in the urine may be readily detected in this manner. At the same time the patient SELENIUM AND TELLURIUM 1 49 will complain of a continuous bad taste in the mouth. At this point the selenium ad- ministration should be discontinued until the selenium is no longer excreted, and then the selenium compound may be given a second time in small doses and at longer intervals. Histo-chemical studies have shown that se- lenium is assimilated by the tissue cells, and principally by the cells of a malignant neo- plasm. Following this fixation of selenium a diminution in the size of the neoplasm and of the malignant character of its cells may be noted. Furthermore, a fact of extreme importance in dealing with advanced cancers is that selenium administration is character- ized by a decrease in the intensity of pain. During the administration of selenium we have found it wise to gradually diminish the amount of morphine taken by the patient, be- cause the intake of morphine is a disturbing factor, and, in fact, after a time the adminis- tration of morphine may become unnecessary. In dealing with malignancies of the blad- der, hematuria is either a constant or in- termittent factor. The administration of selenium often decreases this hematuria. Most probably this is due to an astringent action of the compound. I50 CANCER We have observed the effects of selenium on inoperable cases, and also following opera- tion in cases of extensive malignancy, as well as in cases of comparatively mild cancerous invasion, such as a small epithelioma of the skin; and we believe that it has properties which, if thoroughly understood and studied, will result in its administration universally and extensively to prevent the occurrence of pain in pre-cancerous cases, and to relieve the pain and retard the growth of those cases which are further advanced. It has been sup- posed to render certain inoperable cases oper- able, but so far such cases have not come un- der our direct observation. We have used several different preparations of selenium. Some of them have a depressing effect upon the heart, as has been previously mentioned, and the various cyanides of se- lenium should not be administered internally on account of the latter effect. Selenium may be used in the form of an inunction, in an ointment base, to obtain its constitutional ef- fects; if so desired it can be used for that pur- pose, as there are at the present time on the market some preparations of selenium with an easily absorbable ointment base, combined with vanadium. This is, however, a somewhat SELENIUM AND TELLURIUM 151 uncertain method of administration and it is locally irritating when it comes in contact with an ulcerated surface. As a result of our investigations we recommend the internal ad- ministration of colloidal selenium. Colloidal selenium has been furnished us in the form of a tablet combined with a physiological salt, in which it is stated that the sodium of the salt has been replaced by potassium; there is one and one-half milligram of colloidal selenium in each tablet. We believe the po- tassium salts are the best for this purpose. These tablets give no depressing after-effects. They should be administered in somewhat the same manner that mercury is given for syph- ilis. Ordinarily the dose should be increased until the toxic effects of the selenium are ap- parent; two tablets after meals, three times a day for one week in the beginning, then one tablet three times daily for one week until the system becomes saturated with selenium. By this we mean that the degree of oxidation will be continuous, theoretically, as shown by its effects in reducing the amount of neutral sulphur in the urine, which should be ob- served weekly for this purpose. Any toxic effects of selenium generally show themselves by a garlicky odor to the breath and the pa- 152 CANCER tient will complain that everything has a char- acteristic taste of the odor mentioned. If its use is pushed further, general depressing effects may be observed on the system, to- gether with an increased amount of pain, which will previously have been noticed to di- minish or disappear, and an increased amount of neutral sulphur will make its appearance in the urine. Our experience, so far, has not always borne out just the results which might be anticipated, as mentioned above; enough sulphur examinations associated with selenium have not been made by us to enable us to make a positive statement as to its effect in that respect, but in certain cases in which we have made these examinations the above con- tention has been borne out. In all cases in which we have administered selenium, irre- spective of the preparation of selenium which has been given, there has been a diminution of pain following its administration so marked as to lead us to believe that it does have a direct action in that respect. Also, while we have seen such toxic effects as a garlicky taste follow the prolonged administration of the colloidal selenium, we have never seen any bad after-effects, while we have seen gratify- ing results so marked as to make us believe SELENIUM AND TELLURIUM 1 53 that it does have, in certain cases at least, a marked constitutional effect for the better. At the same time we have no desire to recom- mend it as a cure-all, but within the lines fol- lowing the laws under which its effects ap- pear, benefit will undoubtedly follow its administration. We have used it previous to operation, in a far advanced case that refused operation, without any apparent result; but its continu- ous use following operation, consent having been given later, in the same case, which showed a tendency to malignancy to occur in the old scar, has been attended with good re- sults, apparently a complete recovery taking place. In another case following operation and radium for malignant growth in an extensive area, recurrence has taken place, its use has apparently in some way arrested such prog- ress and restored the individual to a com- paratively healthful state. In a far advanced case, such as reinvasion following the operation for the removal of both breasts, and extensive involvement of the chest wall at the back, it has apparently re- tarded further progress. In such conditions as inoperable cancer of the bladder it has been 154 CANCER found useful to relieve pain and for the con- trol of hemorrhage, thereby making the pa- tient more comfortable and apparently re- tarding the progress, but without curing the individual. We have experimented with selenium com- pounds from three different manufacturers. The one from which we have obtained the best results and which we are at present using is manufactured by E. C. Steinach, of this city, and can be obtained of Munsch, Protz- mann & Co., 410 Madison Avenue, in the form of tablets, which, it is stated, contain one and one-half milligrams of colloidal selenium, with about one grain each of chloride of po- tassium and sulphate of potassium. They also prepare the solution of potassium seleno-vana- date, as well as some of the salts of tellurium. Selenium is fortunately an inexpensive prod- uct to obtain, but the preparations should not, we have been informed, be manufactured from selenium that has been heated to a great extent, and care should be used to free the metal in the process of manufacture from all impurities. Tellurium, like selenium, has the property of oxidation in the animal organism. It be- longs to the same group as sulphur and se- SELENIUM AND TELLURIUM 1 55 lenium. Its action is somewhat milder, and it therefore has to be given in much larger doses. Its toxic effects are much less than in the case of selenium, but they are harder to detect after the system is saturated, unless by chemical tests of the urine. It is an oxidizer, the same as selenium, and is recommended in cases where the neutral sulphur is present to a very great extent. This is a much rarer element than selenium. The metallic tellurium at the present time upon the market varies anywhere from 20 per cent to 75 per cent to 95 per cent balance im- purities; and while the salts are more stable than those of selenium, they are more difficult to prepare, tellurium being a less active ele- ment. It combines with the earthy elements like potassium, sodium lithium, to form solu- ble salts, which can be obtained in a reason- ably pure state. Tellurous acid salts have been given in five-milligram doses three times daily. Per- sonally we have had no experience with its internal administration, but when taken to any considerable extent it sometimes produces a dermatitis, which fact renders the thera- peutic use of tellurium valueless. In car- cinomatous conditions tellurium may be best 156 CANCER employed as telluric acid, applied locally in an antiseptic solution. (See chapter on Anti- septics.) Every tumor ought to be removed sur- gically if suspected to be malignant. Inves- tigation of the urine as regards sulphur should be made previous to operation. The surgical removal of the tumor should also be followed by selenium administration. The success of the procedure surgically and the internal administration of selenium cannot be judged until some two or three years following the operation. However, if a recurrence follows in the old scar or as a result of metastases, this cannot be readily detected by a disturb- ance in the sulphur excretion. CHAPTER VI Preparations for Cleansing, Deodorizing, AND Disinfecting Cancerous Lesions OF THE Skin Practically all who have been in attendance on those suffering from ulcerated surfaces of the skin associated with cancer, if the ulcera- tion was of any extent, have felt the need of some application that would place the ulcer- ated areas in a more healthul condition, and at the same time disguise or remove the un- pleasant odor associated with them, a prepa- ration not intended to act as an active destructive agent, like arsenous acid paste, previously mentioned, radium. X-ray, or excision ; but for the purpose mentioned above we recommend Dakin's solution as prepared by Killian's formula, or the paste dichlora- mine T. The formulas for the manufacture of both these preparations are presented in this chapter. The medical profession is in- debted to Dr. Alexis Carrel for work done, both abroad and at the Rockefeller In- 157 158 CANCER stitute, for popularizing Dakin's solution. Before giving these formulas it may be well to review briefly what action it is desired to obtain by their use, and the reasons for the same. Nature has two defenses against infection. The first, the number of antibodies normally present or developed; and second, phagocy- tosis assisted by opsonins. These are the pre- cise periods to remove infection. The anti- bodies start in from one to two hours from the period of contamination, up to twelve hours. The phagocytosis begins when the line of demarcation has been established between healthy and diseased tissue, and lasts for a longer period of time. The first thing to be done is to remove the necrosed tissue, because it is at this time that antiseptics find their greatest usefulness. The most common anti- septic used is carbolic acid (crude), intro- duced by Lister. Its power of asepsis is good, but it also destroys tissue. In the cancerous ulcerations the period of contamination has passed before the patient comes under our observation. The proper preparation to be used is one which contains some of the qualities of a germicide (which destroys micro-organisms), of an antiseptic ANTISEPTICS, ETC. 1 59 (which works against sepsis), or of a disin- fectant (which is used to combat infection, or to do away with it). The antiseptics are divided into: (i) phenolic; (2) metallic salts, HgCl2, HgNOs; (3) dyes; (4) halogens, e. g.^ iodine, etc.; (5) miscellaneous, e. ^., hydrogen peroxide, alcohol, etc. Of all these the chlorine group has given the greatest satisfaction. Chlorine Compounds. — There are four available chlorine compounds, of which two at present are widely employed. All of the chlorine compounds have chlorine in active form, loosely bound and readily given up. Attention is called to the fact that the prin- cipal test of chlorine is the liberation of iodine from KI. Some of the formulas are as fol- lows: r>u^ ' ( chloramines Chlorme 4 ^ , . • ( hypochlorite Chlorine united to N N-Cl N(g mono- di- In studying the action of hypochlorites upon protein substances, H was replaced by chlorine, forming chloramino-acids. Chlor- l6o CANCER amino-acids are antiseptics. The principal hypochlorite preparations are Dakin's solu- tion and eusol. To prepare eusol, bleaching powder and boric acid in equal parts are taken, water added, and filtered. These solu- tions make an alkaline mixture. Ca(OH)2 and carbonate and Ca(OCl)2 and a little HCIO. These are very easily prepared. Formula for eusol : 1 2.5 gms. Ca(OCl)2 12.5 gms. boric acid 1,000 c.c. water. Dakin's solution must be neutral; 0.5 per cent NaOCl. When used in a stronger solu- tion causes irritation, and below this is in- efficient. Methods of making solution: 1. NaoC03 + CI2 (gas). 2. Ca(OCl)2 + Na2C03 + NaHCOs. 3. NaOCl + (from Ca(OCl)2 with Na2C03) boric acid. The last of these three is the best. Boric acid as a polybasic acid is more effi- cient in the neutralization of antiseptics than neutralization with sodium carbonate. In the preparation of an antiseptic we must get our ANTISEPTICS, ETC. l6l measure at a point where it gives a red color with alcoholic phenolphthalein, and no color with solid phenolphthalein. If it becomes too alkaline it destroys not only necrosed tis- sue, but also healthy tissue, and consequently hampers the neighboring tissue cells in their protective action against the invasion of any infection. On the other hand, if it is not suf- ficiently alkaline, its keeping properties are so very poor that it deteriorates two hours after preparation. In the action of antiseptics on necrosed tis- sue the chlorine combines with the nitrogen, forming chloramino-acids. Consequently the mixture takes on an acid reaction, but the alkalinity of the antiseptic will neutralize this acid. In certain types of infection, and this is particularly true of those concerned in can- cer, the mixture is more likely to become alkaline, and we must therefore have some compound in the antiseptic capable of neu- tralizing that alkalinity. For that purpose we have chosen as a substitute for boric acid, telluric acid. Telluric acid belongs to the same chemical group as boric acid, and it is likewise a polybasic acid. It therefore, like the phosphates and carbonates of the blood, has a true buffer action, covering a wide 1 62 CANCER range of hydrogen ion concentration. More- over, telluric acid, or the salts of telluric acid, when used in moderate quantities, stimulate epithelial cells in their protective action against infection or the invasion of malignant cells. For the making of the antiseptic we follow the formula for Dakin's solution, where the sodium hypochlorite is prepared from chlorinated lime and sodium carbonate. This is rendered alkaline to phenolphthalein, and then telluric acid is added until the mixture gives no color with solid phenolphthalein. This requires very little telluric acid, and the keeping properties of the mixture are very good. Application of the Antiseptic To obtain the best results with the antisep- tic, the wound is saturated every two hours, and between applications smears are made of the exudate. The smears are stained with Loeffler's menthylene blue, and the bacteria to a high-power field counted. The average of some ten fields is taken as a safe indication of the degree of infection. The antiseptic is applied until the number of bacteria is greatly diminished, that is, to one or two to a high- ANTISEPTICS, ETC. 1 63 power field. It will be noted at this period that the amount of exudate is very small. The wound, moreover, has taken on a healthier appearance and the invasion of neighboring parts has stopped. In some cases, as, for in- stance, in carcinoma of the breast, the appli- cation of the antiseptic continually may cause irritation. In that case it is wise to dilute it with an equal quantity of distilled water and apply more frequently. It is also to be recommended that if the antiseptic is to be kept for any length of time, that potassium permanganate be added, to the amount of 5 milligrams to a liter, to add to its keeping qualities. If a paste is desired, and in some cases, as in epitheliomata of the face, where constant irrigation without injury to other structures, as the eye, is impossible, the most valuable paste is that prepared by adding to sodium stearate dichloramine T, plus sodium arsenite. Dichloramine T may be made from sodium sulphonamide by adding hypochlorous acid, or preferably by adding to the sulpho- namide sodium hypochlorite and heating until the solution is obtained, then adding acetic acid. A white crystalline precipitate is ob- tained, and this is taken up in the stearate as a vehicle and the arsenic is added. One gram 164 CANCER of the arsenite is added to 100 grams of the dichloramine paste. One application of this paste in twenty-four hours is sufScient. Un- less some unforeseen condition should prevent, when using it, the Dakin's solution should be kept constantly applied by means of the tube, placed in the dressing in the manner in which it is ordinarily used. After the ulceration has been put into a healthy state, as mentioned above, then the wet dressing can be removed, and probably the washing off of the ulcera- tion once a day through a glass syringe will be enough to keep it in a healthy state. Par- ticularly in cold weather, it may be enough for such conditions as cancer of the breast, when it is not advisable or convenient for the patient to be confined to bed, to apply the paste instead of the solution once a day after the ulceration has reached a healthy state. In summer, on account of the tendency of the stearate to decompose, the paste had better not be applied over any extensive surfaces. The disagreeable odor will be disguised by the chlorine present in the Dakin's solution, and after the ulceration has reached a more healthy state, will cease of its own accord to be present, as the conditions which give rise to it will have been removed. ANTISEPTICS^ ETC. 1 65 The above two preparations we recommend more highly than any other as the best local applications for cleansing, deodorizing, and disinfecting these ulcerated cancerous sur- faces, but even where their action is attended with pleasing results, too much reliance should not be placed on them alone, but every en- deavor should be made, through the internal administration of selenium or whatever me- dicinal preparations may be used, to take advantage of this opportunity to combat the disease by their internal administration and to use every other climatic and hygienic meas- ure which is at the command of the attendant. The formula for eusol is given in this chap- ter because it is easier to prepare than Dakin's solution and can be used in place of it when the latter is unobtainable. Where it is im- practicable or impossible to employ all of the technique which we recommend as associates with the application of Dakin's solution, such as the examination of the smears under a high- power microscope, the attendant can use the preparations recommended, if found to be of benefit, according to his best judgment. Naturally it is easier to use these preparations in institutions which are properly equipped for pathological and chemical work. Unfor- 1 66 CANCER tunately, even to-day not infrequently institu- tions, otherwise well equipped for the care of individuals suffering from malignant dis- ease, are very poorly fitted out in the above two particulars. Every two hours is sufficient to apply the solution through the tube. In this manner the dressing of gauze is kept con- stantly wet. In cases where, in spite of all possible care, the application of Dakin's solution or the paste' is found to disagree, there are, as previously mentioned, a great variety of antiseptic solu- tions or unirritating ointments that may be applied for the same purpose. Our experi- ence has been that ordinarily the best results are obtained by the weak and less irritating germicides; solutions of aluminum acetate or lead and opium wash are sometimes useful. Boric ointment or an ointment which is at present on the market which contains tellu- rium and selenium, under the name of Un- guentum Sel-Van-Sen, may be tried around the edges for the purpose of preventing fur- ther infection and with the idea of absorption of the selenium by the system. The Dakin solution, modified according to the Killian formula, either plain or diluted, can be used, and its effects observed, on can- ANTISEPTICS, ETC. 167 cerous ulcerations on mucous membranes, either as a douche or a wash. Great care should be used, however, in using this solu- tion around the face where there is an oppor- tunity of its being inhaled, as the chlorine might prove irritating to the lungs. CHAPTER VII General Considerations As has been stated, this little work is the combined efforts of a chemist and surgeon working together, both of whom have studied the cancer problem from their respective standpoints for several years. Some of the conclusions which have been presented are the result of the work that both of them have done, in association with homes for the relief of incurables, or as a result of observations made in hospitals, in the wards of which the most far advanced cases are apt to present themselves, being filled with the most de- pendent of all of a large city's population. Therefore, to a very great extent, the conclu- sions are founded on observations made on the most difficult cases. This work has in- tensified our belief in the value of what can be done for the relief of, or at least the re- tardation of the advance of the processes in earlier cases, when an accurate diagnosis has once been made, by the use of measures often i68 GENERAL CONSIDERATIONS 1 69 neglected, which we have at the present time, while expecting the discovery of some new remedial measure, possibly a serum, which will cure this condition in a semi-miraculous manner. We have learned not to expect too much from such preparations as tuberculin for tuberculosis, or from mercury or salvarsan in syphilis, although the use of these two lat- ter have been of invaluable aid ; and we should not expect too much from any sudden cure for cancer. Just the same, in carcinoma we predicate that even now astonishingly good results can be obtained from the careful and persistent use of measures which we have at our com- mand. The history taking is of the very greatest importance. In any case where there is the least ground to suspect malignant growth, in taking the history due regard must be paid to the fact that slow mental reaction follows questioning in many cases. It may be necessary to ask the same question over and over again, particularly concerning the cause of death of collateral relations of the indi- vidual who is being examined. Clinically such a condition has been observed by us as a marked increase of neutral sulphur in an individual of a distinguished family, where a I JO CANCER careful family history had been kept for one hundred years, and in whose family is re- corded the death of eleven persons from can- cer, the common ancestor being the patient's grandfather. In such individuals a careful history- recording will in time prove not only of aid in the diagnosis of any individual case, but continued careful history-taking will eventually help clear up some of the points in connection with heredity in this disease. Much still exists that can be accomplished in the future by observations of the records of the various countries, as shown by the report of the health officers, and the discovery of those regions where cancer does or does not exist. Our observations so far are that neither climatic conditions nor racial charac- teristics have any effect outside of the influ- ence they may have on general hygienic con- ditions, but that heredity is a powerful factor which is always to be considered. Life in the open air, particularly for individuals in whom cancer is diagnosed in its earlier stages, can- not be too highly commended. Contrary to the opinion of many, we regard the question of diet of secondary importance, providing digestible food in sufficient quantities is ob- tainable. The diet can be modified somewhat GENERAL CONSIDERATIONS 171 according to the exigencies in each individual case. Everything should be done to cheer, en- courage, and calm the mental state of unfor- tunate individuals so affected, and all meas- ures of a material, social, and spiritual nature that are practical should be adopted for this purpose. So far as we are able to ascertain, cancer differs from syphilis, in the earlier stages of the latter disease, in the fact that it is not contagious, and probably in that respect from tuberculosis also. It is a question whether the somewhat com- plex question of cancer and marriage should be discussed in a work of this description, which is intended to be of a scientific char- acter. It is desired to touch as little as pos- sible on either philosophical or religious grounds. The three, however, are sometimes so dependent on one another that it is impos- sible to discuss them separately. Naturally, individuals of either sex with a malignant growth clearly demonstrable will refrain from marriage. It may be expected that an increas- ing number of individuals will be discovered as sufferers from a pre-cancerous state, either by the use of methods for diagnosis which are 172 CANCER just now commencing to be applied, or by increasing refinements in that direction from future discoveries. These people can prob- ably be cured of a condition, when once it is recognized, by the careful adoption of every hygienic or medicinal measure calculated to increase and sustain proper tissue metamor- phosis for at least two years. They can at least be relatively cured to the extent that indi- viduals are relatively cured of other similar conditions, such as tuberculosis; and they probably will not transmit, to the extent they have received it, the tendency toward the de- velopment of malignant neoplasm. It is fair to hope that it is in accord with the laws of heredity (and apparently it is to the extent known to us) that through these measures it can eventually be bred out of the system, just as now, if we can go by the records that are already being presented to us, it is being bred in; and that in the future, and probably not far distant future, its frequency of occurrence will be very materially diminished. ^CUGv. >-vr-H-