Speaking for more than 1,000 active committee members who carry on the work of the American Cancer Society here, I wish to assure you of our interest in any legislation designed to further cancer research and control. S. 1875, which is before you for consideration, would make funds available in ample amount to attack this problem adequately. However, we believe that certain amendments should be made. Will you consider these changes and make recommendations when an opportunity presents, if you agree that our reasoning is sound? 1. There should be no time limit on the expenditure of $100,000,000 as now stipulated. We believe that great waste would ensue if the entire sum had to be spent within the 5-year limit called for by the bill. 2. This money should be spent by, or under the supervision of, an already nationally established agency such as the National Research Council (whose committee on growth passes on research grants for the American Cancer Society), or the United States Public Health Service, already experienced in cancer research through its National Cancer Institute. 3. Grants-in-aid to the States also should be spent by, or under the supervision of, already established State agencies such as the State Department of Public Health, State Cancer Commission, or State affiliates of the American Cancer Society. It would seem wasteful to ignore the experience of agencies already interested in and working on cancer control. Anything you can do to bring about the enactment of S. 1875, with these changes, will be greatly appreciated. Sincerely, FRANCES HESS State Commander. EXHIBIT 49 BERKELEY, CALIF., July 13, 1946. The Honorable Senator CLAUDE PEPPER, United States Senate, Washington, D. C. DEAR SIR: With reference to the Pepper-Neely bill in support of cancer research and discussions thereanent, I take the liberty of bringing to your attention the following facts and making a few suggestions. "There can be no independent decision in any area of public policy unless men have the courage to state their ideas and then subject them to rigorous and discriminating criticism."-Harold Stassen. 1. The training of cancer experts need not postpone worthwhile research. It must be conceded that civilization influences toward cancer, including so-called occupational cancer require not only the research of the physician per se but that of scientists of other branches of knowledge, such as the agricultural chemist. In fact, I recommend the closest interdepartmental group work on the widest scale. There is a possibility that modern artificial fertilizing methods may conduce to cancer through a lack of tracer elements. The spraying of fruits of the field may upset the living equilibrium between the beneficial and hostile organisms of the soil. Doctor Gerson's dietetic results in cancer treatment might find a solution by the investigation of the pathological enzyme formation so frequently responsible for cancer growth. It is a known fact that the enzyme formation is closely linked with mineral metabolism. It is clear that in this field not a cancer specialist but the enzyme chemist would be the logical chief research man. 2. Prevailing statistics of successful cancer treatment need revision. Beneficial results in cancer treatment present a gloomy picture as it is. In a true picture based on realistic statistics there would be almost total darkness. Yet to understand what confronts us and correctly gage progress, statistics at all times must be as nearly correct as possible. I allude to this matter in my article entitled "New Salvage Surgery for Cancer." I now recommend that in cancer statistics there should be excluded all skin cancers and all localized cancers that are only microscopically and not clinically diagnosed. Moreover, I think the evaluation of the statistics. should not be left to the individual statistician but to objective committees composed of retired surgeons and X-ray men at suitable salaries. It has been remarked that older men are de trop, that only the young can understand the young. I disagree with this assertion. Resiliency of mind does not depend on age but the nature of the mind itself—and this applies to research in all phases of any type of research. 3. Though citizens of the United States should organize and direct all investigations, congressional funds appropriated for cancer research should not be limited exclusively to American cancer specialists and scientists. The cure for cancer is not an American dream. The affliction is worldwide and almost everywhere men are seeking for the final solution. It would' be criminal to disregard the vast potential foreign help. The effort should be international under American leadership. Moreover, abroad there exist conditions more favorable to cancer research in certain respects than in the United States. I refer to the greater facilities for experimentation on humans' and availability of autopsy material in certain countries of Europe. Salaried American scientists should be sent to these countries with funds sufficient to insure the collaboration of competent experts native to those countries. 4. Obstruction to research by the ultraconservative should be eliminated. It is almost a truism that the rigid conservatism of some scientists in leading social and economic positions still retards progress. If possible, these men should be exposed for neglecting overt possibilities much in the same way that a high military officer is censored for failing to seize opportunities in the field of battle. One and every promising lead should be thoroughly tested without hindrance by the reactionaries and, when due, proper acknowledgment should be accorded the man doing the pioneer work. 5. In time the United Nations Health Organization should be the main coordinating agency. Only thus will it be possible to marshal effectively all the research forces not only of the United States but all other, countries toward a concerted world-wide effort to combat a common enemy. I That other countries are eager to participate is without question. had personal experience of this recently through the unsolicited recognition given me by the Mexican Cancer Society. Narrow nationalism has no place in such a vital undertaking as cancer research. "If a man wishes his country to prosper but never at the expense of other countries, he is at the same time an intelligent patriot and a citizen of the universe."-Voltaire. Sincerely yours, NEW SALVAGE SURGERY FOR CANCER ERIC KOSTER, M. D. By Eric Koster, M. D., Berkeley, Calif., Honorary Member, Second Mexican Cancer Congress, 1946) "Nature cannot be governed, except by obeying her."-Francis Bacon. The very limited success of radical extirpative surgery as well as of palliative measures in cancer forces salvage surgery into the foreground. Howe and Shapiro estimate that radical surgery is successful in only 18 percent of all cases. They stress the importance of salvage surgery, but do not offer any new ideas. Such an attempt will be made here. The proposed reforms of the surgical procedures are based on the following two clinical experiences which are interrelated: First, it is an established fact that a large primary tumor is less conducive to metastases than a smaller one. Secondly, in prolapsed organs in which cancer per se is rare (Benecke, Kennedy), the course is extremely benign, the spread always being arrested. This is my own original observation. Two cases will prove my point. The first case has been reported by Koenig. Here, the cancer was found in a ptotic stomach, the large tumor being located in the left hypochendrium. This patient was found well 12 years after resection. My own experience is limited to a totally prolapsed cervix in a 70-year-old woman. In this case the specimen, after vaginal hysterectomy, proved to be an arrested, well-localized cancer, despite many years' duration and exposure to continuous irritations. The elongated cervix had an elephantoil appearance. According to Drinker and Yoffey, malignancies in elephantoil regions are not common, as the rare malignant degeneration in indolent varicose ulcers proves (Behan). Moreover, Benecke has observed that asthenic individuals with long mesentaries and ptotic viscera rarely develop cancer, nor persons with varicose veins and scoliosis. To pyramid a vast edifice as this recommended salvage surgery upon two pin points of clinical experiences, is, to say the least, an uncommon procedure. "If the two principles are completely true and the deductions are entirely valid, all is well," in the words of B. Russell; "but the structure is unstable and the slightest flaw anywhere brings it down in ruins." * * * That is why it has taken me about 20 years to eliminate some of the flaws. The main objective of salvage surgery is the formation, as the first stage, of an artificial prolapse whenever this is possible, or a similar effective procedure, producing a permanent combined venous and lymph congestion of the tumor and the entire adjacent regional lymph drainage area. Prolapse formation has already been employed, for instance, in recto-sigmoid cancer, but merely for technical reasons to relieve tension in later sutures in connection with the anastamosis. I wonder if the long survival and frequent revival of the Paul-Miculicz procedure has not been influenced in some degree by the beneficial effects of the prolapse formation itself. It must be observed, however, that abdominal exteriorization never imitates a natural prolapse completely, for the lymphatic-vascular pedicle in a natural prolapse is stretched in a downward direction. Only in sacral exteriorization (Babcock and Kuettner) is natural prolapse duplicated. In our recommended procedures the exteriorization principle itself is only of secondary importance. In all obstructive and also nonobstructive cases of cancer of the digestive tract, defunctionalizing complete exclusion procedures (distant from the cancer growth) should always be exécuted in combination with prolapse procedures. Moreover, certain details have to be observed. The stretching of the vasculo-lymphatic pedicle should narrow the thin-walled veins without obstructing their lumen. In this way a limited circulation is maintained for a while. The arterial circulation should be kept as intact as possible. In cases of doubtful arterial supply, symphatectomy should be added or arterial hyperemia by mechanical means. Arterial hyperemia without simultaneous prolapse formation in the treatment of cancer is dangerous (G. Spiess). A mere obstruction of major veins by ligation is not sufficient to accomplish the continuous combined venous and lymph congestion of the prolapse, because it does not cause permanent efema when not associated with extensive thrombosis. Bier's intermittent venous hyperemia, therefore, has no place in cancer surgery, being even dangerous because it is not permanent and does not produce lymph congestion. The effect of the prolapse formation is comparable to a vacuum cleaner arrangment because leading gradually to a beneficial reversal of the lymph circulation. This vacuum cleaner arrangement will render unnecessary prophylactic dissections of regional draining lymph nodes. In surgical borderline cases it opens up the possibility of later radical removal of the tumor mass. The gradual enlargement of the prolapsed tumor mass can be spoken of as a ripening process. It was thought that ripening, as for instance in parotid tumors, would make a complete removal easier and allow for better protection of the facial nerve. However, one of the real advantages of ripening is that it counteracts a too rapid regression of the primary tumor with its dangerous complications. The accelerated spread. which follows arterial starvation treatment (Theilhaber) supports this contention, because arterial ligation leads to rapid regression. Therefore, when arterial ligation at later stages becomes necessary for controlling hemorrhages, at the ligation of the hypogastric artery in cervical cancer and of the carotid artery in advanced head and neck lesions, such ligatures should always be combined with procedures which are capable of producing venous and lymph congestion. Woglum observed that tumor mash upon entering the circulation in large amounts leads to absorption of the antibodies of the body fluid and in this way interferes with the adequate function of the regression immunity. On the other hand, ripening of the tumor improves retrogression immunity. For Lumsden observed that the regression immunity is greater after the retrogression of a tumor that is large rather than one that is small. The demarcation trend of the prolapse is another advantage. It allows for a preservation of all regional reticulo-endothelial structures without compromising on the final complete eradication of the tumor mass itself. The favorable influence of an unspecific hyperplasia of regional lymph glands, following infection upon cancer development, is a proof for the value of regional defense mechanisms. It is known that lymphocytes play a role either as carriers of antibodies or as active producers of antibodies or both. In contrast to this valuable regional defense, local resistance is only of little significance in cancer. It is, however, an effective aid in infections, as Buchner has pointed out. In infection the enemy invades, as it were, a well-prepared terrain, defended by an experienced army. The inflammatory process therefore represents the local manifestation of a general mobilization plan that strives to isolate the invaded part from the rest of the body until the danger is over. Cancer growth, on the other hand, may be likened to the work of a fifth columnist force. Naturally, such hidden enemy easily escapes early detection and thereby makes early diagnosis difficult. In a long preparatory campaign this force gradually undermines the resistance of the organism. Borst therefore rightfully called cancer a fight of brothers against brothers. The fifth columnists are derived from cell groups endowed with potential immortality. They belong to the endless chain of multipotent or totipotent cells, which because destined for high specialization, are equipped to hold energy reservoirs. Such potential cancer cell groups, originating from sex cells or their offspring, persist in higher vertebrates only in certain locations as in the germinative zones of the stratified epithelium or in the primary physiologically indifferent zones of a single-layer epithelium (Schaper-Cohn), and here only in relatively small numbers. In lower vertebrates they occur throughout the organism as unspecialized tissue (Berryl). When such cell groups, caught in well vascularized heterotopic formations (own observation), become physiologically isolated (Childs), they are slowly fertilized by their own stagnating metabolic and excretoric waste products. They gradually develop like overripe frog eggs, losing the power of differentiation and acquiring a tendency of forming tumors (Wischi). This is due to an enzymatic disequilibrium of the antagonistic differentiation and plastic hormones (as is shown in bone fracture experiments by Bier, Fraenkel). Disequilibrium between vitamin B1 (deficiency) and excess of estrogenic hormone seems to play some role in the genesis of cervical cancer. Because enzymes themselves are metabolites, one naturally has to expect a new crop of enzymes adapted to the peculiarities of the heterotopias. These adaptive enzymes initiate the break in the internal control mechanism of the cell, discernible in the disintegration of the normally interlocked forces of function, nutrition, and growth. Step by step increases the growth momentum lead to an autonomous existence of the cells with an unrestrained cell proliferation. The power to invade the adjacent epithelial tissues (not the connective tissue-Schiller) is due to new, more destructive probably bound portions of enzymes acting as an autocatalyctic substance, possessing the pass-key (Rulf). Their disastrous effects are naturally more pronounced in the proximity of the site of the origin of the tumor. From this described carcinogenesis it is evident that the term clinical cancer should not be applied when no true regional involvement is present. Statistics, including cases of pure local involvement, are prone to be misleading. The Conversely, the distant, discrete metastatic foci do not show the same aggressive vitality because they represent only secondary daughter cell colonies. removal of distant metastases when isolated as in the liver, is justified as part of salvage surgery when combined with artificial prolapse formation of the primary tumor mass. What influence the complete eradication of the primary tumor mass. may exert in regressing multiple auto-sensitized foci, future observation should indicate. Naturally, the traumatic or inflammatory origin of the heterotopia leads to a damaged mesenchyme, as such a deficient mesenchyme is later incapable of exerting restraining influence on potentially aggressive epithelial cells. Ribbert showed experimentally that displaced epithelial cells without connective tissue develop in a disorderly manner. When an abundance of connective tissue is present, an orderly development results. The predilection places for cancer (Pick) are examples of the role of a weakened mesenchyme in the carcinogenesis. Another example is the state of subinvolution in which mesenchymal relaxation (Auflockerung) prevails. Normally, the involution process releases mesenchymal protective mechanisms against the ever-present danger of fifth columnists. One of such effective mesenchymal reactions is the overproduction of elastic tissue, observed by Pick and others in the involutional breast and uterus. A healthy elastic tissue is an efficient barrier against the permeation of cancer cells. Consequently, one sees in cancer only infrequent, and then only rudimentary, attempts of mesenchymal local defense. Lymphocytes and plasma cells, when present in the neighborhood of a tumor, can be relied upon as signs of increasing resistance (Da Fano). In the retrogression of a tumor an increase in lymphocytes has been observed, while in active growths the lymphocytic reaction normally remains low. On the other hand, the lack of local resistance in cancer growth does not mean that a slow regressing tumor mass cannot be useful in furnishing properly graded antigens so essential in initiating regional and systemic reticuloendothelial defense mechanisms. Combined venous and lymph congestion, as brought on by prolapse formation, provides the necro-hormones (Caspari) which are regarded as potent stimuli for the functional activity of the reticulo-endothelial system. Interesting in this connection is the stastically bolstered assumption that skin cancer furnishes protection against visceral cancer. Moreover, all general measures that stimulate the reticulo-endothelial system, such as small doses of X-ray and ultra-violet radiation of the spleen (Ruskin), and Bogomolets serum have some place in salvage therapy. Frequent sunburns, which seem to furnish a certain immunity against later cancer development, probably do that by stimulating the reticulo-endothelial system. The protection of the regional and systemic reticulo-endothelial structures from X-ray and radium damage is one of the most important tasks. Cancer cells die continuously in lung and spleen (A. Fischer), and therefore these organs, as long as they remain uninvaded by caner cells, should not be weakened by artificial means. Pneumonitis, as a complication from deep X-ray therapy in breast cancer, is a case in point. In this connection I recollect two cases of X-ray damage to the salivary glands with subsequent disastrous results. The applications were for such precancerous conditions as leucoplakia of the tongue and tooth fistula after an extraction. In each instance the X-ray and radium treatment seemed responsible for very rapidly progressing and finally fatal malignancies. Both were characterized by increasing anaplastic changes, characteristic for a damage of the regional defense mechanism. Massive blood transfusions containing concentrated differentiation hormones I would have been worth while trying in these cases of such increasing anaplastic recurrences. It is known that the most specialized tumors proliferate slowest and are therefore least malignant. But because many instances are recorded of normal secretory functions persiting in malignant tissue, not too much should be expected from the attempts to force differentiation in general carcinosis, when attempts are not combined with all the other here recommended therapeutic methods. Surgical methods which may aid in activating reticulo-endothelial defenses are as follows: 1. The ligation of the splenic vein is to be recommended when it can be easily accomplished as in stomach resection. Experiments speak in favor of such ligation because it produces marked immunity against subsequent tumor inoculation (Auler and Nagumo). 2. Ligation of the pulmonary veins may be considered in unfavorable cancers of the inferior cava vein drainage areas before the lungs are invaded. The purpose would be to change the tissue equilibrium in the lungs in favor of the mesenchyme. It is interesting to contemplate that such pulmonary venous ligation imitates a well-developed pulmonary throttle mechanism in those animals that lack an efficient hepatic throttle mechanism. 3. A reversed Eck fistula (Biebl) is another suggestion which would help to shunt the blood from the inferior cava vein circulation into the portal vein circulation with its more abundant supply of reticulo-endothelial barriers, imitating cases with varicose veins. |