H. J.

Heimlich: Malaria as a Treatment iot

MALARIA AS A TREATMENT FOR CANCER

by

Henry J. Heimlich, M.D.

Professor of Advanced Clinical Sciences

Xavier University

Cincinnati, Ohio 45207-1096

submitted for publication in

Science

May 9, 1986

from the Heimlich Institute at Xavier University

supported by a grant from the Fannie E. Rippel Foundation

 ABSTRACT

Malariatherapy, the pre-antibiotic neurosyphilis treatment of choice that

continued in use for nearly thirty years after the introduction of penicil

lin, deserves a trial in the treatment of cancer. Induced malaria has prac

tical and theoretical advantages over mechanical modalities and surgical

procedures that produce regional or whole-body hyperthermia and are cur

rently utilized in an attempt to modify host response to malignant tumors.

Malaria rarely coexists with cancer. Clinical remission of malignant dis

ease following malaria infection has been reported. Carcinoma is infrequent

in malarial zones, and cancer rates rise as malaria incidence declines

within a geographical region.

KEYWORDS

malaria

malariatherapy

hyperthermia

oncology

cancer

immunity

parasitology
 MALARIA AS A TREATMENT FOR CANCER

INTRODUCTION

Temporary induction of malaria is experimentally justifiable in

cancer patients after failure of standard therapy. The logical development

of the concept began in the 1950's after observing that palliative electro-

cautery treatment of a patient suffering from non-resectable carcinoma of

the rectum was followed by gradual remission of the neoplasia. Electrodes-

sication of the central portion of that cancer was repeated every few months

to control blood loss and to keep the rectal passage open. Two years after

the first treatment, the rectum was surgically removed, and there was no

metastatic spread of cancer found in the abdomen. Ristopathological exami

nation of the resected specimen showed relatively few cancer cells embedded

in scar tissue.

Expecting to find reports of occasional serendipitous responses to

cauterization of tumors in the medical literature, I was intrigued to en

counter large series with similar results. ~ Cauterization has long been

known to provoke systemic rejection of neoplasms, with gross and microscopic

anatomical examination documenting the isolation of residual tumor within an

envelope of fibrous tissue. Such favorable modifications of the biological

response appear to represent a hyperthermia effect initiated by the applica

tion of heat to tumor cells in situ.

The use and acceptance of the cauterization of tumors has been lim

ited. Therapeutic elevation of body temperature, however, is an established

modality utilized in combination with other forms of treatment to combat

malignant neoplasia. Knowledge of the complications and limitations of

mechanical techniques for inducing hyperthermia and the relative convenience

of malariatherapy for treating neurosyphilis led me to suggest malarial

9 10
hyperthermia for treatment of cancer. ' Further reviews of the liter

ature, statistical studies, and animal research provided additional indica

tions to proceed with cancer malariatherapy.

In October 1984, as visiting professor at the University of Illinois

at Chicago, I was privileged to deliver the Twelfth Annual Alfred A. Strauss

Memorial Lecture. My lecture, entitled "The Concept of Malarial Hyperther

mia for the Treatment of Cancer," was a fitting tribute to Dr. Strauss, who

had published a monograph preceded by at least eight papers about carcinomas

of the colon and rectum treated by surgical diathermy. '

 HISTORY OF CARCINOMA REMISSIONS UTILIZING HYPERTHERMIA

Bacteria and Toxins

It has long been appreciated that bacterial infections and elevated

temperatures destroy cancer cells. As early as 1891, cancer patients were

deliberately infected with erysipelas. By 1893 William B. Coley was using

streptococcal and other bacterial toxins to induce fever. In the United

States, the major pharmaceutical firm of Parke, Davis and Company marketed

and distributed Coley toxins from 1899 through 1951 (with modifications in

14 15
1906 and 1915). Helen Coley Nauts ' has thoroughly documented the

history, the therapeutic rationale, and the worldwide manufacture and use of

the toxins her father devoted his professional life to developing. Striking

cures were recorded despite inconsistency of the febrile reactions and de

creasing effect with acquired immunity. Recent work, including Nauts1

review of 449 clinical cases, confirms that bacteria and their toxins di

rectly damage cancer cells and inhibit metastasis.

Cautery

Published scientific papers have long demonstrated that the results

of hot cautery destruction of various cancers are better than when excision

is performed with a cold knife. Strauss cites Byrne's report of 1889

describing a twenty-year experience with galvanocautery for carcinomas of

the uterus as well as Czerny's paper of 1899 reporting similar observations

after use of the galvanocautery knife to resect cancers of the tongue. By

1910 Kolischer, as chronicled by Strauss, ' ' advocated surgical dia

thermy for the removal of malignant bladder and colon tumors and posited

that electrocoagulation not only produces mechanical destruction of the tu

mor but also works "by throwing off into the circulation certain substances

and antibodies which immunize against further progress of the disease."

Five different groups of surgeons reported using cautery to treat

more than 700 patients with cancer of the rectum prior to 1967 and achieved

cure rates considerably higher than those following standard cancer opera-

2 3 11 12 18 19
tions. ' ' ' ' ' Having participated in the development of surgical

lasers during the 1960's, I submitted a research grant proposal in 1972 to

the National Cancer Institute to investigate laser-induced intralesional

hyperthermia in malignant tumors of the esophagus, not only for palliation,

but as a potentially curative procedure.

THE CONCEPT OF CAUTERY AS HYPERTHERMIA

Recent reviews of hyperthermia for treatment of malignant disease-

refer to whole-body or regional heating techniques but do not include the

5-8
use of laser and electrosurgical diathermy resection and destruction. I

submit that the differences between the modalities may be merely quantita

tive/ that the similarities outweigh the differences: cautery produces a

wide range of temperature variation for a short time in a circumscribed

site, while regional or whole-body hyperthermia techniques produce rela

tively small but prolonged elevations of temperature throughout the body or

body part. The unpredictable consequence of a modified biological response

will manifest itself after a delay measured in weeks or months following

either regional or whole-body hyperthermia or surgical cautery treatments.

Animal experiments by Strauss and co-workers ' confirmed that cau

terization of a primary lesion can yield cures in cancers chat have pro

gressed beyond the limits of resectability. After transplantation of the

Brown-Pearce rabbit testicular tumor, cauterization of a portion of the

tumor was followed by disappearance of the primary tumor with resolution of

generalized carcinomatosis and immunity to subsequent challenge for at least

two more years. Cauterization of normal tissue, on the other hand, had no

such effect. Similar but less definitive results were obtained with sponta

neous mammary tumors in white rats. The authors postulate the production or

liberation of circulating immune substances following heat destruction of

cancer cells. By 1979, the Heimlich Institute at Xavier University was per

forming animal experiments to evaluate the effects of local hyperthermia and

pulsed magnetic fields upon murine tumors. Those studies of cancerous mice

further demonstrated the curative effects of heat for the treatment of

cancer.

The reason why metastatic lesions sometimes disappear after cauter

ization of tumors has never been determined. During the discussion of his

1971 paper, Madden mentions sending blood serum samples from his patients

to the National Institutes of Health where no serological evidence of spe

cific immune response was found. He declares: "I have never seen any

evidence of an autoimmune response in the treatment of rectal cancer by

electrocoagulation." Greco ' and co-workers demonstrated no detectable

cellular immunity in their patient groups, but report that "electrocoagula-

tion is associated with less immunosuppression than abdominoperineal resec

tion. "

Surgical cautery and fulguration involve the intense and localized

delivery of heat in temperature ranges high enough to produce instantaneous

23
combustion or vaporization of living tissues. It seems unlikely that

substances provoking the sought-after rejection response would come from

tissue that is completely charred or that is quickly cut away and removed

during a procedure in which the laser or electrodessication electrode is

used primarily for surgical ablation.

Thermal gradients and critical temperatures attained may explain the

generalized effect of cautery hyperthermia. The temperature decreases with

distance from the cauterized site, intermediate temperatures ranging from

those causing incineration through normal or ambient subnormal. It is logi

cal for the disease-altering effect to require the presence of a cancer cell

at some depth from the cautery. Cellular reaction or disruption occurs at

an appropriate distance along the thermal gradient, conceivably liberating

an altered or denatured substance that functions as an antigen to tumor '

cells, to oncogenes, or to unrecognized accompanying pathogens.

Whole-body or regional hyperthermia may thus be a logical extension

of the brief and intermittent use of surgical cautery. An advantage of

whole-body hyperthermia in comparison with cautery or diathermy techniques

is that prolonged or repeated elevations of temperature more nearly within

the physiologic range can affect tumor cells throughout the body without
immediate tissue destruction. All of the tumor degradation components thus

remain continuously available to exert their antigenicity and thus prolong

the opportunity for activation and participation of the immune system.

THE EFFECT OF HYPERTKERMIA ON CANCER CELLS

Studies with viruses that produce tumors after they infect animal

cells show that malignant transformation occurs only after a series of pre

liminary stages. Some of the steps involved require the active partici

pation of complex and occasionally thermolabile molecules and processes

24 25
related to permissiveness and genomic integration and expression. ' At

California Institute of Technology, Fried isolated a mutant polyoma virus

sensitive to heat in its ability to replicate. At 31.5° Celsius the virus

was found to produce either transformation or productive infection, depend

ing on the type of host cell; at its nonpermissive temperature of 38.5°,

however, such expression of the viral genome was impaired. A number of

viruses are cold-sensitive for the maintenance of malignant transformation

of cells in culture: in an extreme example, a single cell can become malig

nant when inoculated with a virus at 31.5°, but will become normal in ap

pearance and in function at 39°, reverting to malignant form if again

brought to 31.5°.27'28

Although there is no necessary correlation of heat sensitivity to a

cell's degree of differentiation or to its state of normalcy or malignancy,

cancers begin to die off at elevated temperatures that leave normal tissue
 5—8 29
intact. ' The relative heat sensitivity of tumor cells relates to ambi

ent acidity, to the tumor's vascularization and blood flow, to alterations

in the physicochemical characteristics of the cell membrane, to oxygen and

energy supply within the cell, and no doubt to other unrecognized fac-

5-8,28-31
tors. Some of these characteristics are also intimately involved

in cellular susceptibility to malignant transformation by viruses. ' '

Many of these variables can be influenced by thermal, metabolic, or pharma-

cologic manipulation of the host. For example, an intravenous infusion of

hypertonic glucose can be used to increase the ambient and intracellular

hydrogen ion concentration (i.e., to decrease the pH) within a neoplasm

while normal tissue is relatively unaffected. The differential in pH can be

clinically significant since an increase in tissue acidity renders cells

more susceptible to destruction by hyperthermia. '

THERAPEUTIC MALARIA

Rationale

Researchers and clinicians claiming a degree of success in treating

cancer with hyperthermia use a variety of physical methods for the delivery

of externally generated heat. For therapeutic benefit, a fever of 41-45°

must be attained. Techniques include encasing the patient in plastic blan

kets through which warm water is circulated; a hot paraffin wax bath; radio

frequency, microwave, and ultrasound energy; and whole-body or regional

perfusion, heating the patient's blood outside the body, then returning it
to the circulation. The equipment and its utilization are costly and com

plicated. In most instances, the patient is subjected to general endotra-

cheal anesthesia, the treatment is severely debilitating, and common compli

cations and morbidity include burns of normal tissue.

Malariatherapy, well standardized for the treatment of tertiary lues,

produces fever more easily than do mechanical means. Wagner-Jauregg of

Vienna first systematically employed malaria for the treatment of neurosyph-

ilis in 1917, for which he won the 1927 Nobel Prize in medicine and physiol

ogy. Due to its high success rates even after failure of other modalities,

malariatherapy for neurosyphilis continued with some modifications after the

development of antibiotics, and was used in combination with penicillin as

late as the mid-1970's.33"37

The technique for inducing malaria with a selected plasmodial strain,

providing care, and using drugs to cure the disease is therefore well estab

lished, as are the morbidity and complications to be expected. Deaths

rarely occurred. Plasmodium vivax, an organism producing benign tertian

malaria, was shown to be the mildest and most easily controlled. In some

patients immune to this organism, a quartan strain was used; human or simian

strains of other plasmodia have also been used. In fifty years of malaria

therapy for neurosyphilis carried out throughout the world, there was no

known report of inability to cure the malaria with appropriate medication.

Presumably, such success was due to proper selection of parasitic strains

32-41
and to omission of the invertebrate sexual cycle.
 c c ..

Malaria fever is as effective for destroying spirochetes as are high

er body temperatures produced by external or mechanical heating techniques.

42
Frederick T. Becker writes in Boyd's malariology text: "Solomon (1938)

found that induced malaria produced twice as many remissions in cases of

general paresis as did physically induced fever." Furthermore, the thermal

death point of the spirochetes is a temperature of 42-45° maintained for one

to six hours, whereas a series of tertian or quartan febrile attacks each

lasting two to ten hours and attaining a fever of 39-40° suffices to kill

all of the syphilitic treponemes. Natural fever may be more effective than

that which is externally induced, or perhaps malaria evokes iiranunological

mechanisms that help kill off pathogens rendered vulnerable by periodically

39
recurring attacks of fever. Recent work not only demonstrates a number of

cellular alterations involved in the immune response to malaria infestation,

but also indicates the participation of "non-specific factors" in the immune

. . 43-45
mechanisms.

Whatever the reasons for malaria's special enhancement of the hyper-

thermia effect against spirochetes, any given temperature attained during a

malaria paroxysm would be the equivalent of externally induced fever 2.5-5°

higher if such relationships were found to hold for cancer cells. Neither

human patients nor their tumor cells often survive temperatures maintained

at 42-45 for hours at a time; using more readily tolerated temperatures

within the physiological range, malarial hyperthermia may suffice to elimi

nate cancer cells the way it kills spirochetes.

 a • u • ntlIliaH.li; noiaua ao a * -
------

Epidemiological evidence — lack of coexistence of cancer with malaria

Cancer rates invariably rise wherever malaria rates decline; nowhere

does malaria coexist with a high incidence of cancer. This antagonism or

inverse proportionality is maintained even within a country where malarial

zones alternate with non-malarial areas subject to identical record-keeping

measures.

Formal analyses of age-adjusted World Health Organization cancer

incidence data for all countries making such statistics available show the ",

lowest cancer death rates to occur in malarial countries. Data from the

World Health Statistics Annual edition of 1979-80 is equivalent to that of c^j

1982-84 (reflecting deaths in 1976-77 and 1980-81, respectively): the ^,

former reports data from 42 countries, of which the six with the lowest

cancer rates are malarial; the latter provides data from 47 countries, the

ten with the lowest cancer rates having experienced problems with malaria

control. ' Such evidence of questionable reliability begins to assume

significance in combination with the following data found to consistently

suggest the same conclusions.

Studies by N. S. Kraus, as reported by Professor Francesco Giugni,

48
I
of Florence, Italy, show that "cancer mortality ... is almost halved in

those places where malaria is endemic." Giugni further states that "an

identical statistic is obtained from the malarial regions of Italy in com

parison between areas of lowland plains and of the mountains free from

malaria," then mentions similar observations by Wiener in Albania during

 h. o. neiFIUlCn: hcialm as a .leatitchi i<j,. wc.in.c4 , (-u3t; _ ■•

[the epidemics of] World War I and by Zieman who "during a decade of activi

ty and study in malarial zones . . . never observed cases of cancer."

At meetings in New Delhi in 1981 with Dr. V. Ramalingaswami, Director

of the India Council of Medical Research, and Dr. B. L. Wattel, Director of

the National Institute of Communicable Diseases, I learned that four decades

ago when most of the population of India had malaria, cancer was very rare.

By 1980, due to rapid advances in malaria control, fewer than 3 million

(i.e., a third of one percent of the population of India) had malaria, and

there has been a corresponding increase in cancer.

In the northern part of Henan Province in China, the leading cause of

death is cancer of the esophagus. Dr. D. J. Li, former fellow in cancer

hyperthermia at Stanford University and now Professor and Head of Oncology

at the Henan Tumor Institute in China, invited me to lecture there in Hay of

1984 on malariatherapy for cancer. Ministry of Health physicians serving in

the malarial region of southern Henan informed me that there is a very low

rate of cancer in that portion of the province although the peoples, their

diets, and other factors are similar to those in the north.

In Ecuador in 1982, I was informed by Dr. Jorge A. Santiana, Director

of the Cancer Institute in Quito, that they had completed a study of the

medical histories of 3,000 families in the malarial region of the country

for the World Health Organization. Not one family recalled a family member

having cancerl During my January 1986 visit to Guayaquil, no physician

treating a patient with cancer or active malaria had encountered a patient

suffering concomitantly from both diseases.

 n. u. nelfTIi 1'-n: naiana as a

Clinical response of cancer to malaria

The Giugni paper discusses cancer cures resulting from accidental and

deliberate induction of malaria. From a book on transfusion, it cites the

following passage written by F. Corelli and E. Pulitano:

We noted long ago that in cases of inoperable cancer of the

digestive tract (stomach and colon) that with the appearance

of malarial febrile attacks allowed to spontaneously run

their course until the sixth to eighth attack, one can then

observe a general recovery and an arrest of the evolution of

the tumor.

Professor Ferdinando Corelli is reported to have presented a paper entitled

"Malariatherapy in Cancer, with Particular Regard to Cancer of the Esopha

gus" to the First Congress of the Italian Cancerological Society held in

48
Milan in April of 1958.

Giugni acknowledges the pioneering work of Wagner-Jauregg and alludes

to the consensus derived from practical experience in the treatment of

infectious disease:

In clinical practice we see moreover that the interruption of

the infective state can depend not only on the degree of

fever thus provoked, but sometimes on the rhythmical and

timely succession of febrile attacks; that which is assured

48
with the tertian rhythm of malaria.
 r.• >.-. r.tilliili.1,: naiaiia ao a

MALARIA, EVOLUTION, AND IMMUNITY

Consistent host-specificity attests to antiquity of malarial para

sites in the evolutionary process. Modern-day lizards are parasitized, as

were, conceivably, the dinosaurs of the Mesozoic era, with consequences open

to speculation. A large variety of vertebrate animals (including amphibians

38
according to older taxonomies, as well as reptiles and a large cohort of

birds and mammals) is infested by at least 120 known species of plasmodial

parasites residing, reproducing, and proliferating inside host cells. In

every known instance, the protozoan sexual cycle with fertilization and

genetic recombination is completed within a culicid (or phlebotomid) insect

serving as the definitive host. Multiplication within vertebrate tissue is

restricted to asexual schizogony resulting in commensal parasitism capable

of prolonged persistence with or without signs and symptoms of disease.

With perhaps some rare exceptions, (e.g., passage from mother to offspring

during pregnancy or live birth) natural transmission of the disease requires

the bite of a bloodsucking insect (although not necessarily that of a mos-

37 38
quito or fly enabling sexual sporogony). '

The evolution of our species was undoubtedly affected by the constant

and continuous presence of such protozoan parasites inhabiting the blood

cells, not only of our ancestors, but also of competing species and of ani

mals consumed for food and used in agriculture. Within the vertebrate host

species serving as a continuous reservoir of infection, the natural selec

tion of individuals carrying what we now consider to be hemoglobinopathies

such as sickle cell anemia and the thalassemias resulted from the survival
or reproduction advantage of parasitic resistance. (In areas where the

parasites are not endemic, such conditions shorten the life span without

serving any useful purpose.) Had these metabolic defects not conferred

antiparasitic adaptations of opportunistic benefit, the extinction or numer

ical suppression of their carriers would have been certain.

Physicians generally believe that malaria produces iiranunopathology

evidenced clinically by non-reaction to tetanus toxoid, and by increased

susceptibility to Burkitt's lymphoma and to Epstein-Barr virus. Such

conventional wisdom is refuted by the facts that malaria has been proven to

cure syphilis and that cancer and malaria apparently do not coexist. More

over, certain malaria patients have a high prevalence of HTLV-III/LAV anti-

49
bodies, yet fail to develop acquired immune deficiency syndrome. Although

this finding has been considered by some researchers to be related to an

immunosuppressive state similar to that occurring in AIDS, it may equally

well indicate an immunostimulation effect that deters the ravages of AIDS.

Heimlich Institute Research Associate Gerson C. Carr, H.D. suggests

that the widespread existence of malaria parasites may be part of a protean

biological process common to terrestrial life, that malaria research dis

closes genetic and epigenetic information capable of solving mysteries

related not only to human disease, but also and more generally to the life

processes and ecology of times past and present. Among many possibilities

are the consequences of gene exchange between hosts and parasites as de-

50
scribed by Howell.
 H. o ■ fceitnucn: Naiaric as d iieauiienL iui notice,

DISCUSSION

Invasion of the body by individual living cells that proliferate

without initial confinement or restraint is the most important pathogenic

event in both malaria and cancer. Neoplasia can be considered a form of

parasitism from within the host, and fundamental interrelationships between

malaria and cancer may still await discovery. A deeper understanding of the

basic unicellular processes seen in both classes of disease may be obtained

by investigating interrelationships between malaria and neoplasia.

Such evaluations require that investigations be conducted in man,

rather than in experimental animals. In addition to the fact that malarial

organisms are host-specific and do not necessarily produce the same reac

tions in all host species, the lack of similarity of human cancers to arti

ficially induced veterinary pathology is commonly acknowledged. Renato

Dulbecco now advocates expending whatever major international scientific

effort may be required to complete the basic research task of sequencing of

the human genome as a requirement fundamental to understanding human oncol

ogy. There is a limit, for example, to the analogies that can be drawn from

studying viral oncogenesis occurring overnight in cultures of undifferenti-

ated cells derived from animal ovaries or embryo kidneys. Although rapid

progression from normalcy through pre-malignant to malignant status does

occasionally result from genomic amplification in man, such aggressive

behavior is exceptional for human cancer. The slow progression of anaplasia

routinely seen during the development of human malignancy is evidence that

malignant transformation is a process of greater complexity than the

 H. «J. heinuicn:

variably thermolabile succession of events following the viral infection of

animal cells in culture as described above.

CONCLUSIONS

Malaria probably is, or until recently was, the world's most preva

lent human disease. It is naturally associated with recurrent episodic

fever, with infestation of the red blood cells, with immune response, and

with changes in the hemopoietic tissues. Available data show that most

malarial zones of the world have a low incidence of malignant tumors, that

the eradication of malaria is followed by an increase in cancer rates, that

patients with malaria are unlikely to develop cancers, and that some ad

vanced malignancies regress following accidental or deliberate infection

with malaria. Although malaria can be eradicated without regard for cancer,

the converse may not be within our immediate reach even after it becomes

possible to compare a tumor's genomic sequencing to that of the definitive

normal human genome.

The combination of malarial whole-body hyperthermia and possible

evocation of immune mechanisms produced by deliberately-induced infection

with benign tertian or quartan malaria deserves a trial, not in lymphomas

known to coexist with malaria, but in such (primarily solid) tumors as meta-

static squamous cell carcinoma and adenocarcinoma of the alimentary canal

and other viscera. Malaria readily aborted with drugs should be induced by

injection of trophozoites (i.e., transmitted via blood rather than by

 H. J. Heimncn: Maiaria as a 'irea-unem. 101 ■- <uav.e -_u-

mosquito sporozoites). It is appropriate to carry out such treatment stud

ies in patients with otherwise incurable cancer. If successful, such treat

ment will be widely available and inexpensive.

 H. J. Heimlicn: Maiaria as a i

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 H. J. Heimlich: Malaria as a Treatment :or Lancer, pciye -*j-

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