1893 W. B. Coley - detailed historic account Tracy XI

In January, 1893 W. B. Coley, a young New York surgeon treated his first case of cancer with the mixed bacterial toxins of Streptococcus pyogenes and Bacillus prodigiosus (now known as Serratia marcescens). This bedridden male, aged 19 had an inoperable sarcoma of the abdominal wall and pelvis (16X13 cm.) involving the bladder with incontinence. Only biopsy had been performed. Injections in or near the tumor caused reactions up to 40[degrees]C or more, and complete regression occurred in four months. He remained well until death from a heart attack 26 years later. (1)


 Back in 1939, when we began our analysis of Coley's method the following questions needed to be answered: was there sufficient clinical and experimental evidence to justify the conclusion that the method had therapeutic value? If so, what factors governed success or failure? Why did the method not achieve wider recognition? If the conclusions to these questions warranted further study we asked ourselves what can be done to make the Coley's toxins consistently effective in most types of neoplastic disease. (2)

Factors that seemed vital to success or failure

1. Variability of preparations used

No comprehensive textbook on the method had been published by Coley, although he was working on one at the time of his death in 1936. He made every effort to obtain unequivocal diagnoses by eminent pathologists from the beginning. However he did not recognize the great importance of obtaining potent, stable preparations of the mixed toxins to avoid variability from different formulae or from batch to batch. (1,2) Coley had no bacteriological training at all and relied on others to make the preparations.

 The first observation brought out by our long-term study was that at least 13 different preparations had been used during Coley's active years, (1892-1936), of which three were considerably more potent than the rest, Buxton VI, Tracy X and Tracy XI. Unfortunately the first two commercial preparations (Parke, Davis & Co.) IX and XII were very weak and the English preparation (Lister Institute VIII) was even weaker, so very few English surgeons achieved success. (1,2) These weaker preparations did not produce adequate febrile reactions. (3) (Figure 1)

In 1902 a patient with recurrent inoperable lymphoma of the pectoral region and axilla reported to Coley that it took 8 minims of the Parke Davis IX to give the same febrile reaction as 1/4 minim of the Buxton VI. (6) Despite such a clear-cut case, Coley does not seem to have attempted to remedy the situation.

Coley seemed to be unaware of this problem until 1911 when he gave a clinical lecture at Guy's Hospital in London and he discussed it briefly in his response to the vote of thanks, ending with the remark "success depends on the preparation...."

Finally in May 1915, Tuholske of St. Louis wrote him about a case of extensive sarcoma of the pharynx and nasopharynx with almost complete obstruction--a tracheotomy was imminent. (1,3) Even massive doses of Parke Davis XII had had no effect at all. Coley then sent him the Tracy XI (see below for details relating to technique). This case made him contact Parke Davis and get them to work more closely with Tracy and so Type XIII was made considerably more potent than XII. (1,2)

2. Technique of administration

Although Coley published 143 papers or monographs on his method between 1893 and 1936, (8) they did not give sufficient detail on how to administer the toxins, i.e. site, dosage, frequency and duration, and the optimum febrile reaction to aim for. The Tuholske case illustrates the importance of these factors. First, the danger of stopping the injections too soon, even if complete regression has occurred. Although complete regression occurred in six weeks, the disease recurred on the opposite side in about three months with evidence of brain metastases. Second, the injections for the recurrence were given subcutaneously or intramuscularly in the deltoid or scapular regions with very poor absorption. Not until given in the abdominal wall did good febrile reactions occur, and the recurrence disappeared, but the symptoms of brain metastases persisted. The patient went into coma for 3-1/2 weeks. No further injections were given. With supportive treatment he regained consciousness and made a complete recovery. He remained well until death from coronary occlusion 33 years later. (3)

a. Duration

Coley himself did not recognize the extreme importance of duration of treatment, especially in the inoperable cases, until 1926 when Christian and Palmer succeeded in curing a reticulum cell sarcoma of the tibia recurrent in the stump after amputation with extensive metastases near the umbilicus and in the left inguinal region. In discussing this case in 1927 Coley stated "I am quite willing to admit that, had the patient been under my care, he would probably not have been alive today.... I am almost certain that I should not have continued the treatment after three months when not only had no improvement been noticed, but marked increase had taken place in the metastatic tumors and especially in the recurrent tumor of the stump (from 17-31 inches). In the second place I am quite sure that I should not have dared to increase the dose to such a large amount (2 cc). However, it was not until these large daily doses were given that the improvement continued until all the tumors had disappeared.... I feel that many of the past failures might have resulted otherwise had larger doses and more frequent injections been given." (1)



 Our end result studies beginning in 1946 have shown that, if the injections were given for six months, 80% of inoperable sarcoma of soft tissues survived 5-88 years. (3)

In osteogenic sarcoma when the Coley's toxins were given as an adjuvant to surgery for at least three months, 85% survived and were traced up to 53 years later. Three other cases so treated died 4-13 years later of late recurrence or metastases, i.e. prolonged survival. If given for less than three months 36-43% survived. This was considerably better than the 10-15% survival from amputation alone in that period. (4)

b. Type of febrile reaction

 Coley also did not sufficiently appreciate the benefit of producing febrile reactions averaging 39[degrees]-40[degrees]C (102[degrees]-104[degrees]F) from the beginning of treatment. This did not occur if they used small doses intramuscularly or subcutaneously remote from the tumor, or when the very weak products were used. This factor was more important in treating inoperable cases. For example, in the soft tissue sarcoma 60% of the inoperable cases, whose reactions averaged 102[degrees]-104[degrees]F with chills, were traced well 5 to 88 years, as compared to only 28% of those having reactions below 102[degrees]F and no chills. (3)

c. Site and dosage injection

The type of reaction elicited depended on two things. The site of injection and the dosage. Injections given intramuscularly or subcutaneously remote from the tumor, required much larger doses to elicit a reaction of 101[degrees]F or more than did an injection into the tumor or in a vascular tissue or intravenously. In the early years Coley used intratumoral injections into different parts of the tumors. These elicited not only fever but tumor necrosis factor and an inflammatory reaction--all of which were more effective in causing destruction of the tumor thus imitating an erysipelas infection. (The most dramatic "spontaneous" regressions of cancer occurred during and following acute erysipelas injections which produce a more intensive inflammatory reaction than any other infection).

 We found only one case treated by Senecal with intraperitoneal injections--a huge ovarian carcinoma with widespread metastases in the peritoneum and ascites. Very dramatic regression occurred in four weeks. The case became operable and recovered. She remained well for 27 years. (1)

Intravenous injections were not used by Coley until about 1925 and usually some intramuscular injections were given first. Very much smaller doses were needed, and these caused no inflammatory reactions. They were well-tolerated.

Fowler in 1898 recognized the importance of site of injection. When given subcutaneously the intensity of the general reaction varied with the dosage. With subcutaneous injections a larger dose was required to produce the desired reaction, whereas a few drops were sufficient for the intravenous route. "The vascularity of the tumors explains the ease with which a reaction can be produced by Coley's method of interstitial injections, the latter being quite analogous, if not identical with the intravenous method." (9)


X-ray and radium were discovered in 1895, only a year after Coley read his first important paper before the American Surgical Association. (8) Coley was one of the very first surgeons in New York to use the X-ray in his practice, and in 1901 he persuaded Memorial Hospital to allow him to procure an X-ray machine there, paid for by one of his wealthy patients. He read his first report on the work before the American Surgical Association in June 1901. (11) The growing enthusiasm of the profession and of patients for both X-ray and radium quickly overshadowed Coley's method before it had been properly standardized or its mode of action understood. Coley then became anxious to prove that the toxins had a systemic rather than local action such as X-ray, radium and surgery, so he stopped using intratumoral injections in 1906, and not until a year or two before he died did he come to realize the mistake he had made.

 d. Frequency of injections

In the early years Coley and other surgeons gave injections daily or every other day at first, which appeared to be more effective than less frequent injections, especially when treating inoperable cases. One surgeon who routinely used the Coley's toxins in both his operable and inoperable cases, Calkins of Watertown, New York, gave the injections daily for about six months, then twice weekly with occasional intervals of rest for another six months. (12) Injections were given as an outpatient after the first two weeks. Calkins achieved 80% five-year survival in using this technique over a 32 year period. Matagne also often gave injections daily (see below).

Many surgeons, such as the Mayo brothers, did not wish to get involved in such long term therapy, so they advised the family physician who had referred the case to the Mayo Clinic to administer the injections after the patient returned home. As a result, a considerable number of Mayo clinic cases were successfully treated.

3. Stage of the disease

 In treating operable cases as an adjuvant to surgery very few surgeons began the treatment prior to surgery. This is unfortunate because preliminary toxin therapy, even for only a brief course, can counteract the immunosuppressive effects of anesthesia and surgery, due to stimulation of cytokines such as interferon, interleukins, tumor necrosis factor and others. In cases of amputation, it counteracts the psychic stress of losing a limb, which is also immunosuppressive.

The first physician to recognize that operable cases might benefit was Matagne of Brussels, Belgium. He first began using the Coley's toxins in inoperable cancers, having observed a dramatic case cured by contracting an erysipelas infection in 1891 reported by Bidlot. (7) In 1896 he gave a rather brief incomplete description of his inoperable cases and was soon criticized by a commission charged with examining it. (14) This did not deter him from continuing his clinical studies and over the next 57 years he published 12 more papers interrupted by two world wars.


 In 1902 he reported on the use of Coley's toxins in operable cases as a means of preventing recurrence, the first physician to do so anywhere. (14-16) In 1905 he presented a series of these operable cancers in which he had administered the toxins before operation, usually for four or five weeks, in some cases for three months. (17)

One extensive recurrent inoperable malignant melanoma of the upper arm in the region of the humeral artery with metastases in the axilla, received injections in the recurrent tumor for seven months in 1902 with rapid but incomplete regression of the recurrent mass, but the axillary metastases did not regress. Shoulder joint disarticulation was then performed. There was no further recurrence and the patient was traced well over 41 years after onset. (15-17)

 Matagne prepared his own Coley's toxins using the effective Buxton VI formula. (17) He gave injections daily into the tumor beginning with a dose of 5 cg., gradually increasing by 2.5 cg. each day or every other day until a febrile reaction of 39[degrees]-39.5[degrees]C. or 40[degrees]C was elicited. The reaction usually consisted of a violent chill which began 30 minutes after injection and lasted 30 minutes. Dosage was increased to 10 cg. in some cases, in others to 30, 40 or even 50 cg.

The first surgeon to save a limb by using Coley's toxins following surgery was Owens in 1894 in a highly vascular giant cell tumor of the proximal tibia following curettage. This was the first case of giant cell tumor in which the limb was saved. (19) In two-thirds of the giant cell tumor cases involving long bones, the limb was saved by the use of curettage and toxin therapy combined, in some cases, with radiation. The remarkable regeneration of bone destroyed by the tumor following toxin therapy was especially evident in Series A, cases 8, 11, 13, 36 and 40. (22)

 Coley himself began using his toxins in operable cases as early as 1895. (20) The first published case was an osteogenic sarcoma of the femur. The patient remained free from recurrence or metastases for 53 years. (4) Other American surgeons soon followed, including Ochsner in 1915 and Calkins in 1917, for breast carcinoma and sarcoma (6) and Meyerding of the Mayo Clinic for osteogenic sarcoma and Ewing's sarcoma of bone. (4)

4. Early criticism: limiting types of tumors treated

Between 1891 and 1896 Coley published 16 papers describing his method. (8) Editorials began to appear in 1894 with the first negative report entitled "Failure of the Erysipelas Toxins." (21) In 1895 Abbe, the President of the New York Surgical Society, suggested that the method be tried in different hospitals, a fair proposal, but no enthusiasm was shown. It is a great pity that such a plan was not carried out, but it is not surprising that a group of surgeons were reluctant to pursue a medical approach to the treatment of cancer.

On October 16, 1895 Coley read a paper before the New York State Medical Association entitled: "The indications for the non-operative treatment of tumors: The value of toxins." This was published in reprint form in 1896. (19) Undoubtedly this report caused more concern among surgeons and a few more negative reports appeared. (5)

 Editorials appeared mostly unfavorable, and Coley responded objectively. On December 29, 1894 he wrote: "That a few physicians in a very limited number of cases with indifferent preparations of the toxins have failed to obtain good results will not ... have great weight in the minds of the scientific portion of the profession in determining failure or success of this method of treatment of sarcoma." (20)

In 1915 Harmer of Boston published a rather comprehensive report on 134 microscopically proven cases treated by Coley's toxins. (21) He concluded that they are of value in certain cases of inoperable sarcoma. He noted that in a small number of cases they produced striking relief of pain. However, his conclusions were rather negative.

 In June 1914 his report included two unusual cases, one a recurrent extensive giant cell tumor of the spine who recovered completely under toxins alone and remained well, until death in 1977 from lung cancer, 65 years after onset. (22) The other was a recurrent malignant melanoma with metastases who under prolonged toxin therapy had complete regression of all the lesions. He then went on a spree for 19 days returning haggard and weak--the disease reactivated and killed him over three years after onset. (21)

Coley's many surgical friends in England and in the United States urged him to limit his use of the toxins to sarcomas since the early experiences with his weaker preparations in advanced carcinomas or melanomas had not proved successful. However, other surgeons had successfully treated metastatic cervical carcinoma, (1) extensive metastatic breast carcinoma, (1) giant cell tumor of vertebrae, (1) recurrent malignant melanoma, (1) ovary, metastatic. (1)

These reports encouraged Coley to use his method on many other neoplasms, testicular cancer, (24) breast cancer, (23) lymphoma and Hodgkin's disease, (25,26) malignant melanoma, (27) multiple myeloma, (28) Ewing's sarcoma, (29) neuroblastoma, (30) colon cancer, (31) and renal cancer, (32) with a great many remarkable results. (1,33)

 5. Animal experiments

In 1907 Beebe and Tracy published the results of their studies (34) in which they stated; "The striking results attained [by Coley] in an increasing number of cases have diverted the attention to the possible significance of the Bacillus prodigiosus in the preparation.... It seemed important to study with some care the effect of inoculation, not only with the Bacillus prodigiosus [now known as Serratia marcescens] but with other bacterial toxins as well with the hope of determining the rationale of this method of treatment, and if possible of placing it on a more scientific basis." They used B. prodigiosus, Streptococcus pyogenes, Staphylococcus aureus and Bacillus communis (now known as Escherichia coli), also the mixture known as Coley's toxins. They treated lymphosarcoma grown in dogs transplanted from a spontaneous tumor, with these preparations.

They reported that B. prodigiosus alone and Streptococcus pyogenes alone as well as the mixture of these two (the Coley's toxins), caused regression of this tumor in the dogs. Staphylococcus aureus given into the tumors caused fever to 105.9[degrees]C, but no real regression. One dog received E. coli causing steady regression: all tumors disappeared in five weeks. They used different sites of injection. The intratumoral injections caused much more rapid regression. (34)

 In conclusion they stated that, "though the action is chiefly local, it is at the same time something more than this for it was repeatedly observed that tumors at a distance from the site of injection undergo regression simultaneously while in one dog all the injections were given remote from the tumor." This paper deserves study. (34)

6. Radiation and toxin therapy

X-ray and radium therapy, having been introduced and embraced by Coley and other surgeons, were used without any knowledge of how radiation might affect the patient's ability to respond to toxin therapy, or if there might be an optimum timing for giving these two modalities since no one knew how the toxins exerted their beneficial effects. This was a serious problem. We now know that if toxins were given prior to radiation they potentiated the response of the tumor to the X-ray or radium while protecting the normal tissues from radiation damage (see below).

 Ewing became medical director of Memorial Hospital about 1915 and he was an ardent advocate of radium, a large supply of which had been given to the hospital by Dr. Douglas. Ewing had no interest in Coley's method.

At that time Coley had been appointed chief of the Bone Tumor Service. Ewing insisted that every single ward case should receive radium or X-ray prior to amputation. Despite the fact that Coley believed this to be a dangerous protocol, he had to comply. In 1927 Coley published the end results on 169 cases. (35) Not a single patient so treated had survived, while in his private patients to whom he gave the toxins following surgery, 50% had survived. If injections were given for three or more months to these osteogenic sarcomas, 85% survived four-40 years later. (4) The Mayo Clinic also achieved 50% five year survival in their toxin-treated cases, while other surgeons here and abroad were curing only 10-15% with amputation alone.

Matagne, as well as Coley, became interested in utilizing radiation in his practice and he acquired some radium at considerable expense which he used especially in epitheliomas. Like many other surgeons he felt constrained to use it to justify the expense incurred. This meant he treated fewer patients with the toxins thereafter.

 One of the first cases Coley treated with X-ray therapy was an inoperable lymphosarcoma of the cervical, axillary and mediastinal nodes, with dyspnea and edema of the lower extremities. Marked regression and increased mobility had occurred following toxin therapy alone, but then control was lost and the patient became bedridden, with severe dyspnea. X-ray was then given 4 to 6 times weekly in 1902 causing remarkable regression in three weeks, complete disappearance in six months. No further toxins were given after radiation was begun. The disease then reactivated with hundreds of pea to egg-sized nodules over the entire body. Death occurred in June 1904, 5-1/2 years after onset. Coley believed the radiation had lowered the resistance of this patient to her tumor. (6)

In contrast to this case is the following where too much radiation was not given. An eight year-old boy had had amputation for a fungating Ewing's sarcoma of the fibula with metastases to the inguinal and iliac lymph nodes. (It was later regarded as a reticulum cell sarcoma). Toxins (Tracy XI) were begun immediately after amputation and given two months with marked reactions. Soon after the injections were stopped a 15 cm. mass in the iliac fossa and lung metastases developed. All disappeared after one radium pack to the groin. (10) The child remained well and free from disease until death from an emergency appendectomy 15 years later. (36,37) This case suggests that the preliminary two month course of toxins may have potentiated the response of the tumor to the radiation.

 Unfortunately such cases did not seem to make Coley recognize the value of beginning the toxin injections prior to radiation, or of giving them for a longer period, especially when metastases were present.

7. Radiation protection

About 1958 a number of investigators began reporting on the protective effect of bacterial endotoxins against radiation injury. (39-41) This occurred if injections were given prior to the radiation, optimally 24 hours before.

Thomson (1962) reported that "bacterial endotoxins prepared from Salmonella typhosa, Escherichia coli, Serratia marcescens and Proteus morganii all promoted hematopoietic recovery when given before or after whole body radiation. Post-radiation infection is appreciably reduced, hematopoietic tissues regenerate and survival in enhanced."

 Ainsworth, of the Cellular Biology Branch of the US Naval Radiobiological Defense Laboratory, San Francisco, published several reports, in one of which he noted that low pyrogen doses are known to produce a more rapid rise in resistance to injection than larger doses, i.e. 50 mcg. was not as effective as 2 mcg. of pseudomonas in increasing survival time to lethal radiation. (40)

At our request in 1962, Ainsworth screened the Coley's toxins as a potential radioprotectant on X-irradiated mice. In this experiment the smaller dose was more protective. This experiment was not published. He sent us the abstract:

Effect of Coley's Toxins on Survival of Irradiated Mice

Method: Typhoid-paratyphoid vaccine was used to compare Coley's Toxins since previous data had shown that TAB is highly effective in reducing the radiation mortality in mice. The mice used were CF1 females, 100 days old, weight 19-24 grams. Total body X-irradiation was delivered from a 250 kv Westinghouse X-ray machine operated at 15 ma and a distance of 40 inches. Added filtration consisted of 0.5 mm Cu and 1 mm A1.

 The mice received 700 r on the day following inoculation. The mice were then caged 8 to a cage--each cage containing two mice from each group. Death checks were made once a day for 30 days following irradiation.

8. Further inertia, criticism and hostility, and occasional enthusiasm

Although Coley continued to publish his results and by 1909, 66 papers had appeared in the United States and Europe, the majority of surgeons ignored or criticized his work.

In 1909 his most comprehensive report to date was read before the Surgical Section of the Royal College of Medicine in London (42) and in 1911 he gave an excellent clinical lecture at Guy's Hospital in London. (43) In response Dr. Hall White stated: "... You have just heard probably the most interesting lecture that has ever been delivered in this theatre. Therefore I am sure you will agree with me that we ought to pass a very hearty vote of thanks to Dr. Coley for having spared the time to give us such a treat.... The proposition was carried by acclamation amid a scene of great enthusiasm which lasted some time." Dr. Coley stated: "I am greatly obliged to you, gentlemen. What I have heard led me to believe that British audiences were cold, but I have never in my own country received such a hearty reception as you have given me today. Sir Alfred Fripp tells me that you have tried the fluid in the hospital. The trouble has been that a different preparation is sometimes used. Mr. Mansell Moullin of the London Hospital had five successful cases, and has said he got his successes with the fluid obtained from the Cornell Laboratory [Buxton VI]. Middlesex Hospital had had three failures but in the fourth, they used the Buxton VI and the growth regressed to 1/14 in a few weeks...."

One form of criticism occurred as a response to dramatic cures. Richardson of Boston in reporting a remarkable case he had referred to Coley in 1893 stated: "Skepticism may be so extreme that carefully observed cases are thrown out for one reason or another, though I cannot but think chiefly for the reason that they were successful. In this case Dr. Garland and myself at the time of operation made the diagnosis as hopeless malignant disease of the abdominal wall. Dr. Whitney made a careful microscopic examination of the tumor and reported it as fibrosarcoma." In October 1893 she received local injections daily into the tumor for six weeks with marked reactions Within two weeks improvement was very evident. The patient's general condition suffered but little and she was up and about most of the time. She returned home for Christmas. A second four week course was given in January. Richardson concluded: "The tumor, though as large as a child's head, disappeared.... If a cure by means other than surgical is, from the very fact of cure, declared sufficient proof of a mistaken diagnosis, there seems little use in presenting evidence.... The curative influence of micro-organisms upon malignant growth, whether during the course of an accidental wound infection, or under the influence of deliberate toxin injection is a hopeful indication of far-reaching possibilities for good." (1,3)

 9. Mode of action

In addition to radiation protection and potentiation of tumor response, the Coley's toxins produce fever which we know is beneficial; they also stimulate the reticuloendothelial system, activate macrophages, increase hematopoiesis, increase production of prostacyclin, endogenous interferon, endorphins, tumor necrosis factor, interleukins and growth factors. (44,45) Interleukin-1 for example, induces a profound hypoferremia which assists the patient in withholding iron from the cancer cells. Weinberg has summarized some of the numerous papers in regard to this subject including Torrance et al. (45a,45b)

Certain infections such as erysipelas (13) and the Coley's toxins also stimulate wound healing (1) and regeneration of bone destroyed by tumor. (22) For example, a case of an extensive giant cell tumor of the proximal femur with complete destruction of 17 cm. including the neck and trochanter with pathologic fracture, recovered under Coley's toxins in or near the tumor given for 7-1/2 months combined with two radium treatments. The first was given after one week of toxins, the second seven weeks later. Complete regression of the tumor and regeneration of the hip joint occurred, with 14 cm. shortening; well until death 45 years later of coronary occlusion. A second case involved the neck, both trochanters, with complete destruction of the acetabulum and ischium and pathologic fracture. He received one radium treatment (9000 mch) 3 days before toxins were begun. Complete regression occurred. The limb was kept in traction and the hip joint and femur regenerated without shortening. (22) In another giant cell tumor of the distal radius involving the ulna, the extensive tumor regressed completely under toxins alone and the bone regenerated with perfect function. (22)

 10. Overwork and health

From his earliest years in practice Coley had always taken on many burdens and responsibilities. At Memorial Hospital, of which he became an attending surgeon in 1897, he established the Needy Patient Fund with spasmodic donations from some of his wealthy patients. He sometimes paid some of their bills himself and in 1898 handled over 40 of these accounts. Numerous needy patients were referred to Coley from all over the United States and Canada and he never refused to treat them. He actually did up to 60% of the "free" operations between 1908 and 1913. (46)

 In 1901 he established the Huntington Cancer Research Fund at Memorial Hospital with a $100,000 gift from his patient Mrs. Collis P. Huntington. In 1901 with funds supplied by Archer Huntington he established the X-ray department and managed it for the first year, the Board having refused to provide the funds. (11)

In 1903, at Coley's urgent request, a medical record librarian was appointed to index and organize the hospital records. Coley planned which system to use and ordered the cards from the Library Bureau and obtained the funds for the registrar's salary. "The Medical Board did not think it proper to put the hospital to any expense in this matter." (46)

In addition to Memorial Hospital, he operated at the Hospital for the Relief of the Ruptured and Crippled (now called the Hospital for Special Surgery, of which he became Surgeon-in-Chief in 1924).

 Unwisely he became Chief Surgeon of one of the divisions of the New York Central Railroad and by 1925, this required three secretaries. The time spent could have been devoted to further studies on his method, but he felt he needed the money.

In 1900 Dr. J. Collins Warren appealed to Coley as regards the needs of Harvard Medical School from which he had graduated in 1888. Over the next two years with a good deal of effort, Coley succeeded in getting John D. Rockefeller, Jr. to give one million dollars and Mrs. Collis P. Huntington to give $300,000 towards the new buildings the school sorely needed. They were dedicated in 1906.

In 1916 Coley began helping one of his Yale classmates to plan a rural hospital in Cambridge, New York (The Mary McClellan Hospital). It was dedicated in 1919 and he became its Surgeon-in-Chief. This required weekly visits on Sunday and Monday for years, which meant he had only Saturday and Sunday mornings for relaxation.

All these years Coley continued to read papers and write reports on his toxin treated cases, both here and abroad, the most comprehensive of which was read at the International Cancer Congress held in Brussels in 1913 and appeared as a monograph in 1914. For this he abstracted 80 cases which he had successfully treated and included a table of 125 cases successfully treated by other surgeons. (47) He also published extensively on his experience with hernia.

His health had always been remarkably good, despite developing acromegaly. The first symptoms, severe periodic headaches, occurred while at Yale in 1883. He did not discuss it with any of his friends or colleagues--even Harvey Cushing. Finally in 1913 someone anonymously sent him a book, Acromegaly, a personal experience by an English physician about his own fatal case. This was a cruel shock, for he had not realized he had it. He determined not to discuss it with his wife, or friends, and so faced it alone, determined to work harder than ever. (46)

Hard work did not affect his health so much as the anxiety and stress due to the growing antagonism of Ewing at Memorial Hospital or with the affairs of the Bone Sarcoma Registry which Codman of Boston had organized in 1920 with Ewing and Bloodgood of Johns Hopkins. In July 1920 Codman wrote "You have probably more living cases than any man in the world. That your treatment has a profound systemic effect I have no question, but I am inclined to attribute the successful cases to errors in diagnosis. Yet I must admit you have more to your credit than anyone else."

 Codman had arbitrarily decided that no successful case should be included if the patient had died prior to 1920. He and Ewing continued to write critical letters to Coley. Finally, on February 6, 1922, Codman wrote a particularly galling letter accusing Coley of being distrustful of him or "perhaps too fond of golf" to find time to send the data needed to register his cases. This letter hurt Coley deeply for he felt it was so unjust. He replied the day he received it explaining that Ewing's laboratory had failed to make duplicate slides as he'd asked them to. "As a matter of fact I have played only nine holes of golf since September,... and had to give up several attractive shooting invitations to stay in town and grind, largely on sarcoma of the long bones. I have had nothing but weekend vacations for the last four years." He added "I cannot see what is to be gained by scrapping all the facts on the subject that have been gathered by many observers up to the present moment at the expense of hard and patient labor, and dating all real knowledge of the subject from the beginning of your Registry."

"I did not like your letter to Dr. Packard about his case. It certainly was not worthy of the high judicial standards that certainly should obtain with such a committee as you have organized.... You could at least have omitted your remark that you 'would regard the case as having gotten well in spite of Coley's toxins instead of with the help of them'...."

 Codman replied on February 20, 1911: "I think your rebuke in regard to the Packard case well merited; what I said was not necessary or wise...." (46) but the harm had been done. Financial strains and his son's divorce were added anxieties. Codman's letter was the final straw that precipitated an ulcer with an almost fatal duodenal hemorrhage about February 12, 1922. He never regained his former vigor in the remaining 14 years of his life, and after further traumatic episodes with Ewing or Codman, he had other hemorrhages. The scar tissue from these ulcers caused pyloric stenosis requiring gastroenterostomy in April 1931--done under local.

By 1926 Coley managed to assemble all the detailed data on the 170 cases of long bone sarcoma and 69 cases of giant cell tumor he had treated from 1906 on and published two excellent reviews in 1926-27.35,48 Despite his poor health in those last years he published 25 more papers including one an Hodgkin's disease and lymphosarcoma. (49) (Between 1910 and 1930 Ewing had consistently opposed Coley's publishing his end result studies with hostile criticism. (46))

He read papers in London in 1923 and in 1928, and these prompted English and French surgeons and radiologists to send him some interesting cases who benefited by his treatment.

In May 1934 Codman was Chairman of a Bone Sarcoma Symposium held at Memorial Hospital, and summarized Coley's paper on Ewing's sarcoma of bone stating, "This paper will give great satisfaction to Dr. Coley's many friends who have admired his courageous, tireless fight to overcome the skepticism of his colleagues.... His six registered cases of five year cures are alone enough to sustain his argument.... Just as it seemed justifiable for the Memorial Hospital during the last decade to test out the value of radiation alone in inoperable cases or in patients opposed to operation, so it seems even more indicated that some great clinic should try out Coley's toxins during the next decade. Unquestionably they produce a profound constitutional effect.... It is time for some great hospital to apply its laboratory resources to the wholly justifiable and distinctly hopeful purpose of giving this treatment a fair trial under favorable conditions. Certainly, in cases of Ewing's tumor, one would hardly feel justified in not recommending the use of the toxins. The question of whether also to give radiation is the difficult one. Dr. Coley quite logically suggests that the combination of the two may be a bad one, for the rapid destruction caused by irradiation may open up channels for further invasion. Radiation in small amounts stimulates lymphocytosis, and its use in this way was advocated in 1918 for the treatment of malignant tumors by Dr. James B. Murphy, of the Rockefeller Institute, after some very convincing experimental work on animals. Large amounts of radiation, on the contrary, destroy the lymphocytes whose formation it at first stimulates. A series of cases treated by the toxins without the concomitant use of radiation, in which the blood reactions are carefully followed, might prove of value. There must have been many, many cases in the past treated by these toxins on the hit or miss principle by the family doctor, without careful study, such as is possible in the modern clinic. Yet, under these disadvantageous circumstances, occasional miracles have occurred and in Coley's own undiscouraged hand these miracles have not been infrequent." (46)

 This eloquent and logical plea of Codman's for definite clinical evaluation of the toxin treatment by treating a series of cases with the toxins alone was not heeded. It was all the more convincing because Codman had been definitely skeptical of the value of the toxins until the results recorded in the Registry convinced him of their value.

11. Belated recognition

In January 1931 Coley retired from the Medical Board of Memorial Hospital after 40 years' service. Dr. Burton J. Lee was Chairman of the committee which planned a splendid testimonial dinner on his 69th birthday. It was held at the WaldorfAstoria Hotel and over 200 of his colleagues, friends and family came. Dr. John Finney of Johns Hopkins was toastmaster, and the speakers included Dr. Charles Mayo of Rochester, Minnesota, Dean Frederick F. Jones, of Yale (his classmate in 1884) and his old adversary, James Ewing.

 Preceding the dinner, telegrams, cables and letters had piled up on his desk full of eloquent words of appreciation. Coley's heart was overflowing with wonder and joy at this flood of genuine admiration. He had fought so many battles despite failing health and loss of hearing and financial problems and now they were forgotten.

We wondered if so many moving tributes would not be more than he could bear with equanimity, for he had always been quick to respond to human emotion. We were overcome at the wonderful way he spoke with dignity, sincerity and strength of character. His love and deep feeling for his friends showed in his face. This memorable evening gave him strength to carry on his writing and other activities with renewed vigor.

 A final honor came in 1935 when he was made an Honorary Fellow of the Royal College of Surgeons in England. This moved him deeply and he gave his last paper on that occasion, published posthumously the following year. (38)

12. Progress since Coley's death

After Coley's death in April 1936, his son Bradley L. Coley, MD became Chief of the Bone Tumor Service and he and his associate Higinbotham, continued to produce excellent results with the toxins in Ewing's sarcoma, reticulum cell sarcoma, giant cell tumor and some osteogenic sarcomas of bone. B.L. Coley and Higinbotham served in the Army from 1942 to 1946. Upon their return chemotherapy soon became a priority. The Medical Director, Rhoads, without consulting the Bone Tumor Service, wrote Parke Davis & Company in 1950 telling them to stop making the toxins. At that time a number of patients were receiving them and this was a cruel blow.

 For a time Rhoads had the toxins made at Sloan-Kettering Institute (SKIxiv) and eight reticulum cell sarcomas were successfully treated with this product, combined with X-ray therapy in some cases. In inoperable cases with metastases the limb was saved in all these, one was a Mayo clinic case. (37)

In 1939 we began a half century of study on Coley's work. We found the factors affecting success were very concrete as outlined above, but they had been largely ignored by Coley and most of the other men using the method. Matagne was an exception. He made his own toxins so they did not have to be shipped and lose potency in transit before the days of airmail, and he administered them wisely.

In 1953 we founded Cancer Research Institute, to provide incentive and support for investigators in this field of cancer immunology. The first two investigators we funded were Johnston at New York University and Havas in Temple University. Johnston's laboratory prepared the Coley's toxins for clinical use and for a special study at New York University. (50,51) Havas reported the effects of the toxins on sarcomas in mice. (52, 53)

Between 1954 and 1963 a number of physicians and surgeons became aware of our studies, requested reprints and obtained toxins (Johnston SV). We also sent them detailed directions for administration and toxin therapy record sheets to facilitate analysis of results.

 Successful results were obtained by several including Johnston (50,51) and Rank in Texas, breast cancer (23); Fowler, in Connecticut, multiple myeloma (54) and colon cancer, (31) and Nicholson in Philadelphia, reticulum cell sarcoma. (37)

Following the tragedy of thalidomide in Europe in 1963, the Kefauver bill was passed enabling the Food and Drug Administration (FDA) to establish very stringent regulations regarding clinical trials of new drugs. Though the Coley's toxins were 70 years old, the FDA ruled it was a new drug requiring special permits and endless red tape to use it clinically, hence all those who were using it stopped.

 Despite this terrible blow we continued to assemble data and to edit and to publish 12 monographs after 1963. (8) We also read papers at 11 international cancer conferences. (8)

One study was undertaken with an FDA protocol at Memorial Sloan-Kettering Cancer Center in June 1976 by Kempin et al. (50) Patients with advanced non-Hodgkin's lymphoma were randomized to receive or not receive one subcutaneous injection of MBV five days before each cycle of chemotherapy. There were 40 nodular poorly differentiated lymphomas, 5 nodular mixed lymphomas, 3 nodular histiocytic lymphomas, Stage II, 5 cases, Stage III, 23 cases, Stage IV, 21 cases. Radiation therapy was given to initial areas of bulky disease or to nodal or extranodal sites responding only partially to chemotherapy. The MBV treated patients had a higher rate of complete remission (73 vs 44%) longer duration of remission (p=0.005) and longer survival (p=.005).

 The product they used was made in Germany by Bayer, and they used only subcutaneous injections at infrequent intervals which caused little or no febrile reactions. Despite these factors the MBV did improve remission and survival, although a few years later the survival curves merged due to late recurrences. Thus the study was not continued, although the authors had reported in 1981 that the study strongly suggested a potential role for MBV therapy in the management of these tumors. (50)

Another physician in Milwaukee, Wisconsin managed a regional burn unit for nine years where he used a mixed bacterial vaccine on 3,000 patients to prevent the virulent infections these patients developed. This made isolation and antibiotics unnecessary. In 1972 he began treating cancer patients with his vaccine and in 1986 he reported on 139 cases. They also received BCG and transfer factor--all were advanced cases that had failed under chemotherapy or refused it. (54) His results indicate that combined immunotherapy was well tolerated, safe and that it had a salutary effect on a number of patients. His best results were in lung cancers and in operable breast cancers given as an adjuvant to surgery: none of the 30 cases so treated has died. (55)

13. China programs

In 1981 Guo, a pediatric oncology surgeon at Beijing Children's Hospital became interested in using the method for his patients. He also was impressed by a case of very extensive sarcoma of the thigh that had recovered following a severe staphylococcus infection with complete recovery. (44) He also had read our first monograph (1) which was in the Medical School Library. He wrote us and we provided the end result studies on pediatric malignancies, the directions as to preparing and administering the toxins and kept in close touch. We went to China in October 1983 and brought Guo to New York that fall, so he could visit Memorial Sloan-Kettering Cancer Center's excellent pediatric division. We emphasized the need for more space in the ward, an area for play and more nurses. We also stressed the need to allow the mothers to be with their children as much as possible to reduce stress which is immunosuppressive. We provided the toxins prepared by Havas in Philadelphia for part of the time.

 In the past 7-1/2 years he has treated 49 cases in children. Of the inoperable cases receiving 10 or more injections 8 were successful, traced up to eight years after onset. There were 16 inoperable failures, of whom six received 7 to 10 injections--too brief a period.

Of the 22 operable cases, only two have died, one of which was recurrent when toxins were begun; 12 have remained free from disease up to six years after onset; seven more recent cases remain well and one equivocal case is probably cured but awaits a "second look."

 Guo is the first surgeon since Matagne in Belgium to use the toxins before as well as after surgery. His results indicate how successful this technique can be: he used injections intratumorally, intradermally over the tumor site, and intramuscularly. (57) Guo has also treated a considerable number of adults in another hospital, mostly hepatomas, but it is too soon to evaluate the results.

In Shanghai, at our suggestion, Tang, a very well-known liver cancer surgeon, has been using the Coley's toxins provided by Havas of Temple University. From May 1985 to December 1987 patients received hepatic arterial ligation plus cannulation for 30 consecutive days, including 12 cases with second stage resection, and 34 patients with palliative resection. These cases were randomized. The controls did not receive MBV or mixed bacterial toxins (as the Coley's toxins are now called). One group had Cis-platin, one group had MBV and radiation, one group had all three. The patients receiving MBV had 47.8% survival versus 35% for the controls. In the second look resection 9/25 survived versus 3/20 in the controls. Remarkable lymphocyte infiltration was found in the tumor specimen after second look resection in the MBV cases. They concluded that "MBV is an ideal agent which is cheap, has no side effects and can be given as an adjuvant with surgery, chemotherapy and radiotherapy." They found that "if MBV is given before chemotherapy as a non-specific immune stimulant, it can prevent the immunosuppression." (58)

 14. Conclusions

We believe that the factors outlined in this review indicate why the Coley's toxins never achieved wider recognition. Since the mistakes of the past are now clearly understood and can be avoided, there is a real opportunity to organize cooperative studies not only for inoperable cancers but as an immunoadjuvant to potentiate the response to the usual modalities and protect against their immunosuppressive effects. The Chinese studies have already shown that this is possible.

[A shorter version was read in Rome. Italy, May 1989 at the meeting of the "International Clinical Hyperthermia Society" and will be published.]

Substance           Amount    No. Mice  Picric
Injected            Injected  Injected  Acid Mark

Coley's Toxins      0.05 ml   25        on back
Coley's Toxins      0.1 ml    26        on head
TAB vaccine         0.1 ml    26        on tail
0.9% NaCl (saline)  0.1 ml    26        none

Summary of Mortality

Substance           Amount                   %
Injected            Injected  Mortality*  Mortality

Coley's Toxins      0.05 ml    0/25        0
Coley's Toxins      0.1 ml     2/26        7.7
TAB vaccine         0.1 ml     3/26       11.5
0.9% NaCl (saline)  0.1 ml    24/26       92.3

*No. dead/Total

 References

1. Nauts, H.C., Fowler, G.A. & Bogatko, F.B.: A review of the influence of bacterial infection and of bacterial products (Coley's toxins) on malignant tumors in man. Acta Medica Scandinavia 145: Supplement 276. Stockholm, April 1953.

2. Nauts, H.C., Swift, W.E., & Coley, B.L.: The treatment of malignant tumors by bacterial toxins, as developed by the late William B. Coley, MD, reviewed in the light of modern research. Cancer Research 6: 205-216. 1964.

3. Nauts, H.C.: Beneficial effects of immunotherapy (bacterial toxins) on sarcoma of the soft tissues, other than lymphosarcoma. End results in 186 deteriminate cases with microscopic confirmation of diagnosis--49 operable, 137 inoperable. Monograph #16. Cancer Research Institute, New York, 1975.

4. Nauts, H.C.: Osteogenic sarcomat: end results following immunotherapy (bacterial vaccines) 165 cases, or concurrent infections, inflammation or fever, 41 cases. Cancer Research Institute, Monograph #15. New York, 1975.

5. Coley, W.B. The treatment of cancer. Guys' Hosp. Gaz. 26: 7-14. 1911.

6. Nauts, H.C., Fowler, G.A.: End results in lymphosarcoma treated by toxin therapy alone or combined with surgery and/or radiation (87 cases) or with concurrent bacterial infection (14 cases). Monograph #6, New York Cancer Research Institute, Inc., New York, 1969.

7. Nauts, H.C.: The beneficial effects of bacterial infections on host resistance to cancer. End results in 449 cases. A study and abstracts of reports in the world medical literature (1775-1980) and personal communications. Cancer Research Institute, Monograph #8, 2nd edition, 1980.

8. Nauts, H.C.: Bibliography of reports concerning the experimental or clinical use of Coley's toxins (Streptococcus pyogenes and Serratia marcescens) 1893-1989 (394 references, including 143 by W.B. Coley). Published 1975, 1977, 1980, 1982, 1984, 1985, 1986, 1987, 1988, 1989.

9. Moullin, C.M.: The treatment of sarcomata by the injection of mixed toxins (Coley's fluid). Brit. M.J. London 2: 451. 1898.

10. Coley, W.B.: Treatment of inoperable malignant tumors with toxins of erysipelas and the Bacillus prodigiosus. Trans. Amer. Surg. Assn. 12: 183-212. 1894.

11. Coley, W.B.: The influence of the Roentgen ray upon the different varieties of sarcoma. Trans. Amer. Surg. Assn. 20: 308-309. 1902. (Also in Med. News 81: 542-545. 1902)

12. Nauts, H.C.: Beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy (bacterial toxins) on ovarian and uterine cancer. Cancer Research Institute. Monograph #17. New York, 1977. (122 pp.) and conference with Calkins 1943.

13. Matagne, H.: Premiers essais de traitement des tumeurs malignes inoperables par les toxines de Coley: un cas de cancer gueri. Gaz. Med. Liege 8: 401-402. 1896. (See also; Rapport de la commission gui a ete chargee d'examiner le memoire de M. le Dr. H. Matagne, a Bruxelles, intitule: Premiers essais traitement des tumeurs malignes inoperables par le toxines de Coley: un cas de cancer gueri. Bull. Acad. roy. de Med. de Belg. (Brussels) 10: 275-278. 1896).

14. Matagne, H.; Traitement des tumeurs malignes inoperable par l'erysipele et par les toxines de Coley. Presse Med. Belge, (Brussels) 51: 603-607; 624-629; 633-639. 1899.

15. Matagne, H.: Les toxines de Coley employees dans le but de prevenir la recidive du cancer. Presse Med. Belge 54: 1-3. 1901.

16. Matagne, H.: Presentation de cancereux gueris par les toxines de Coley, employees conjointement avec intervention chirurgicale. Presse Med, Belge, 57: 173-179. 1905

17. Matagne, J.H.J.: Vers la guerison du cancer. Le Scalpel 104: 504-544. 1951; and 106; 1387-1395. 1953.

18. Owens, J.F.: The use of toxins in the treatment of sarcoma, particularly of operable cases. Illinois State Med. Soc. Trans. (Chicago) 218-277, 1897. (also New Orleans, M. & S. J. 50: 1-8. 1897.

19. Coley, W.B.; The indications for the non-operable local treatment of tumors. The value of Toxins. Concord, NH. Rep. Press Assn. 1896. (read before the New York State Medical Association, October 16, 1895. Reprint).

20. Editorial: JAMA Dec. 15, 1894; Coley's reply Jan. 5, 1895.

21. Harmer, T.W.; A study of the efficiency of mixed toxins (Coley) in inoperable sarcoma. A critical analysis of 134 microscopically proven cases. Boston M. & S. J. 172; 331-338; 373-377; 411-416; 440-448. 1915.

22. Harmer, T.W.: Remarks upon the effects observed in the use of the mixed toxins (Coley) in certain cases of sarcoma. Boston M. & S. J. 171: 253-261. 1914.

23. Nauts, H.C.: Giant Cell Tumor of Bone: End results following immunotherapy (Coley's toxins) alone or combined with surgery and/or radiation (66 cases), or with concurrent infection (4 cases). Monograph #4, 2nd edition, Cancer Research Institute Inc., New York, 1975.

24. Nauts, H.C.: Immunological factors affecting incidence prognosis and survival. in breast cancer. Part I: Factors affecting resistance to breast cancer and therefore its incidence and response to treatment. Part II: The immunopotentiating effects of concurrent infections, inflammation or fever. Part III: Immunotherapy, effects of bacterial vaccines. Cancer Research Institute, Monograph #18, New York. 1984.

25. Coley W.B.: Cancer of the testis; containing a report of 64 cases, with special reference to 12 cases of cancer of the undescended testis. Trans. South Surg. & Gyn. Assn. 26; 17-67. 1914. (Also in Ann. Surg. 62; 40-73. 1915).

26. Coley, W.B.: Primary neoplasms of the lymphatic glands including Hodgkin's disease. Assn. Surg. 63: 35-70. 1916.

27. Coley, W.B. & Hoguet, J.B.: Melanotic cancer; with a report of ninety cases. Trans. Am. Surg. Assn. 34: 319-383. 1916.

28. Coley, W.B.: Multiple myeloma. Ann. Surg. 93: 77-89. 1931. (Also in Trans. Amer. Surg. Assn. 48: 489-514. 1931).

29. Coley, W.B.; Endothelioma, or Ewing's tumor. Am. J. Surg. 27: 7-18, 1935.

30. Fowler, G.A. & Nauts, H. C.: The apparently beneficial effects of concurrent infections, inflammation or fever and of bacterial toxin therapy on neuroblastoma. New York Cancer Research Institute, Inc., Monograph #11, New York. 1970.

31. Fowler, G.A.: Beneficial effects of acute bacterial infections or bacterial toxin therapy on cancer of the colon or rectum. New York Cancer Research Institute, Monograph #10, New York, 1969.

32. Nauts, H.C.: Enhancement of natural resistance to renal cancer: Beneficial effects of concurrent infections and immunotherapy with bacterial vaccines. New York Cancer Research Institute, Inc. Monograph #12, New York, 1973.

33. Nauts, H.C.; Bacterial products in the treatment of cancer: past, present and future. In Bacteria and Cancer, eds. J, Jeljaszewicz, G. Pulverer & W. Roszkowski, Proc. International Colloquium on Bacteria and Cancer, Cologne, Germany, March 16-18, 1982. London/New York, Academic Press, 1982. pp. 1-25.

34. Beebe, S.P. & Tracy, M.: The treatment of experimental tumors with bacterial toxins, JAMA 49: 1493-1498. 1907.

 35. Coley, W.B. & Coley, B.L.: Primary malignant tumors of the long bones; end results in one hundred and seventy operable cases, Ann. Surg. 13: 779-836. 1926; 14: 63-141. 1927.

36. Coley, W.B.: Endothelial myeloma or Ewing's sarcoma. Radiology 16: 627-656. 1931. (Also in Trans. South Surg. Assn. 43: 65-95. 1931).

37. Miller, T.N. & Nicholson, J.T.: End results in reticulum cell sarcoma of bone treated by toxin therapy alone or combined with surgery and/or radiation (47 cases) or with concurrent infection (5 cases). Cancer 27: 524-548. 1971.

38. Coley, W.B.: Diagnosis and treatment of bone sarcoma. Glasgow M.J. 126: 49-86; 128-164. 1936.

39. Thomson, J.F.: Radiation protection in mammals. Reinhold Publishing Corporation, New York, p. 178. 1962.

40. Ainsworth, E.J. & Forbes, P.D.: The effect of Pseudomonas pyrogen on survival of irradiated mice. Radiation Research 14: 767-774. 1961 and personal communications.

41. Ainsworth, E.J. The effect of pyrogen dose in radiation protection. Radiation Research 14: 446-447, 1961

42. Coley, W.B.: The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus of erysipelas and the Bacillus prodigiosus). Practitioner (London) 83; 589-613. 1909. (Also in Proc Royal Soc. Med., Surg., Sect. 3; 1-48. 1909-1910. (Abst. in Brit. M.J. 2: 144-145. 1909).

43. Coley, W.B.; The treatment of cancer. Guys'Hosp. Gaz. 26: 7-14, 1911.

44. Nauts, H.C.: Immunology of Cancer--The Pioneer Work of Coley. Presented at: International Symposium on Endotoxin: Structural Aspects and Immunobiology of Host Responses, Riva del Sole, Giovinazzo (Bari), Italy, May 29-June 1, 1986.

45. Old, L.J.: Tumor Necrosis Factor. First identified because of its anti-cancer activity, the factor is now recognized to be one of a family of proteins that orchestrate the body's remarkable complex response to injury and infection. Scientific American: 59-75. May, 1988.

45a. Weinberg, E.G.; Iron withholding; a defense against infections and neoplasia. Physiological Reviews 64: 65-102. 1984.

45b. Torrance, J.D., Charlton, R.W., Simon, M.O. et al.: The mechanism on endotoxin induced hypoferraemia.

46. Coley, W.B.: Office records 1892-1936.

47. Coley, W.B.: The treatment of malignant inoperable tumors with the mixed toxins of erysipelas and Bacillus prodigiosus, with a brief report of 80 cases successfully treated with the toxins from 1893-1914. Brussels, M. Weissenbruch, 172 p. 1914

 48. Coley, W.B.; Prognosis and treatment of giant-cell sarcoma, based on a further study of end results in 69 cases. Ann. Surg. 86: 641-665. 1927.

49. Coley, W.B.: End results in Hodgkin's disease or lymphosarcoma treated by mixed toxins of erysipelas and Bacillus prodigiosus, alone or combined with radiation. Trans. Amer. Surg. Assn. 46: 331-357. 1928. (also in Ann. Surg. 88: 641-667. 1928).

50. Johnston, B.: Clinical effects of Coley's toxins. I. A controlled study. Cancer Chem. Repts. 21: 19-41. 1962.

51. Johnston, B.: Clinical effects of Coley's toxins. II. A seven-year study. Cancer Chem. Repts. 21: 43-68. 1962.

52. Havas, H.F., Grosbeck, M.E. & Donnelly, A.J.: Mixed bacterial toxins in the treatment of tumors. I. Methods of preparation and effects on normal or Sarcoma 37-bearing mice. Cancer Res. 18: 141-148. 1958.

53. Havas, H.F., & Donnelly, A.J.: Mixed bacterial toxins in the treatment of tumors. IV. Response of methylcholanthrene-induced, spontaneous, and transplanted tumors in mice. Cancer Res. 21(1): 17-25. 1961.

54. Nauts, H.C.; Multiple Myeloma: Beneficial effects of acute infections or immunotherapy (bacterial vaccines). Cancer Research Institute Inc., Monograph #13, New York, 1975.

55. Kempin, S. et al.: Improved remission rate and duration in nodular non-Hodgkin's lymphoma (NNHL) with the use of mixed bacterial vaccine (MBV). Trans. Amer. Soc. Clin. Oncol. 22: 514, 1981.

56. Kempin, S. et al.: Combined modality therapy of advanced nodular lymphomas (NL) The role of nonspecific immunotherapy (MBC) as an important determinant of response and survival. ASCO abstract, May, 1983.

57. Guo, Z. & Nauts, H.C.: Pilot study of mixed bacterial vaccine (MBV) on pediatric cancers: 57 cases. In manuscript.

58. Tang, Z. et al.: Experimental and clinical studies on mixed bacterial vaccine in the treatment of primary liver cancer as adjuvant. In manuscript.

59. Waisbren, B.A., Sr. Observations on the combined systemic administration of mixed bacterial vaccine, Bacillus Calmette-Guerin, transfer factor, and lymphoblastoid lymphocytes to patients with cancer, 1974-1985. J. Biol Response Modifiers 6: 1-19. 1987 Also personal communications, 1977-1989.