Sarcoma and HIV
PAPADOPULOS-ELEOPULOS(1), V. F. TURNER(1), and J. M. PAPADIMITRIOU(2)
Medical Hypotheses (1992) 39, 22-29
of Medical Physics Emergency Department, Royal Perth Hospital, (2)
Department of Pathology University of Western Australia
- Recently published informed debate affords strong indication that
in patients with the Acquired Immune Deficiency Syndrome, HIV cannot,
directly or indirectly, be the cause of Kaposi's sarcoma. This paper
provides reasons for disallowing a current alternative theory that
Kaposi's sarcoma is due to an unidentified sexually transmitted
infectious agent and proposes instead that Kaposi's sarcoma is the
result of prolonged and repeated exposure to nitrites and/or semen.
If this alternative hypothesis is strengthened by confirmation of
its predictions then the relationship of HIV to Kaposi's sarcoma,
one of the principal AIDS-associated diseases, becomes somewhat
remote. This may facilitate a shift of emphasis and encourage the
development of alternative therapies.
theory is a good theory if it satisfies two requirements:It must
accurately describe a large class of observations on the basis
of a model that contains only a few arbitrary elements,and it
must make definite predictions about the results of future observations.
In spite of
the passage of more than a century since Kaposi's original description,
Kaposi's sarcoma (KS) remains enigmatic with its precise nature
in doubt. Recently even its classification as a malignant neoplasm
has been questioned and John Brooks, a pathologist from the University
of Pennsylvania, has argued that KS is a "benign potentially
reversible hyperplasia that may at times terminate in true malignancy"
of KS sub-types.
is classified on the basis of pathological,clinical and epidemiological
descriptions (2). Epidemiologically Kaposi's sarcoma occurs as "Sporadic",
"Endemic","Iatrogenic" and "Epidemic"
disease with obvious major differences between these sub-groups.
The "Sporadic" type has a predeliction for Italian and
Ashkenazy Jewish males over the age of sixty years (although in
a series from the Armed Institute of Pathology published in 1959
22% of the patients were black (3)). This sub-type of KS is associated
with a near normal life span. However,some cases exhibit the aggressive
form and there are cases occuring in younger patients under the
age of 45 years (4).
group,which constitutes the highest caseload in the world,occurs
in eastern equatorial Africa. Here KS affects young adults (25-45
years of age) and children between the ages of two and fifteen.
Any of the clinical patterns may occur in this group and there is
an appreciable incidence of the generalized variety in the young
adults and children,most of whom die within two years of diagnosis
(5). Prior to the AIDS era "Iatrogenic" KS accounted for
approximately 15% of all cases enumerated in Europe and North America
(2). These were associated with immunosuppressive agents administered
to organ transplant recipients or to patients with other diseases.
The incidence of post transplant KS in the United States is 0. 18-0.
3% of all transplant patients while interestingly the incidence
in Saudi Arabia is considerably higher at 5. 3% (2). Penn,who reported
a series of 68 post organ transplant cases from the USA, considered
that 72% were "benign"(skin and mucosa involved) and 28%
malignant(gastrointestinal and respiratory involvement) (2). The
reason why KS and also lymphomas occur in these patients while there
is no increased incidence of the common epithelial neoplasms is
unclear. However,in a comprehensive review of this subject published
in 1982 Kinlen discounted failure of immune surveillance and argued
the case for a specific viral- related effect in the pathogenesis
In the early
1980's the Centre for Disease Control (CDC) in Atlanta USA observed
a high frequency, 26 cases by July 1981, of KS occurring in young
homosexual men (4). Eight of these patients died within 24 months
of diagnosis. Thus was ushered in "Epidemic" KS,that associated
with the Acquired Immune Deficiency Syndrome (AIDS). In addition
to KS many of these original patients also had opportunistic infections
and in four a diagnosis of Pneumocystis carinii pneumonia (PCP)
was made by open lung biopsy. At this very early stage in the evolution
of the syndrome,AIDS,for all practical purposes,consisted entirely
of KS and PCP. In 1982 Robert Gallo,who had spent many years researching
retroviruses and cancer at the National Cancer Institute, proposed
that the cause of AIDS was a retrovirus (7). In 1983 Luc Montagnier
and fellow researchers at the Pasteur Institute detected a retrovirus,presently
known as Human Immunodeficiency Virus Type I (HIV-1),in the cultured
T cells from a homosexual patient with lymphadenopathy (8). With
few exceptions (9,10), the hypothesis that the causative agent of
AIDS is HIV has been universally accepted. However,as early as 1984
it became apparent that HIV does not exist in the cells from the
lesions of KS and hence cannot cause KS directly (11). It was assumed
then,that in AIDS patients,HIV indirectly caused KS and opportunistic
infections by its detrimental effects on the immune system. Alterations
in T lymphocyte subsets (T4 and T8 cells) and a decrease in the
T4/T8 ratio were believed to be the hallmark of AIDS and the immune
deficit that defined this condition (7). However, in heterosexuals,
evidence existed that many diverse causes could be associated with
the same (and additional) laboratory abnormalities of immunodeficiency
that were manifest in AIDS patients. These causes included a number
of infections (12),blood transfusion (13),the intake of many drugs
including antibiotics (14) and even solarium exposure (15). It is
noteworthy that in none of these reports was there a single case
of associated KS.
some researchers at the time were of the opinion that KS could result
from immunostimulation with angiogenesis-promoting factors formed
as a result of alterations in immunoregulation,a mechanism that
had been earlier suggested in patients receiving immunosuppressive
therapy (16). As recently as 1988 researchers from the Walter Reed
Army Institute of Research,disallowed KS from the definition of
AIDS stating that,"in our system the presence of opportunistic
infection is a criterion for the diagnosis of AIDS,but the presence
of Kaposi's sarcoma is omitted because the cancer is not caused
by immune-suppression"(17). Most recently data has been published
confirming the fact that in some homosexuals KS can occur in the
complete absence of both immune deficiency and HIV (18). Thus neither
HIV nor immune deficiency is a prerequisite for the development
of this disease,at least in homosexuals.
this uncertainty,acceptance of HIV as the cause of Kaposi's sarcoma
prevailed for over six years until early 1990 (19). In January of
that year Valerie Beral and her colleagues from the CDC published
a paper (20),in which they concluded that "Kaposi's sarcoma
in persons with AIDS may be caused by an as yet unidentified infectious
agent transmitted by sexual contact". This argument was based
on the epidemiological spectrum of KS in different AIDS risk groups
and the fact that in homosexuals KS may appear in the absence of
HIV. This conclusion, to which we cannot accede, is based on the
authors' assumptions that:-
agent that causes Kaposi's sarcoma must be the same irrespective
of whether there is any associated HIV infection". Implying
that KS in all individuals, homosexual or heterosexual, African
or European, black or white, is caused by one and the same agent).
(b) The agent
is infectious but is not HIV.
theory becomes accepted and as a necessary overture to our own hypothesis,
we will present evidence that:-
(a) There is
no need to assume that the same causative agent is responsible in
all cases of KS regardless of age, race or geographic region.
(b) The assertions
upon which Beral and her colleagues base their infectious theory
are themselves only hypotheses which their various authors acknowledge
as being largely unproven and have even suggested alternative explanations.
(c ) There
are plausible explanations for the apparent correlation between
sexual activity and KS in homosexuals other than sexual transmission
of an infectious agent.
It is inconsistent
with current knowledge of other neoplasms to assume that KS is exceptional
by having a single cause in all individuals. At present it is well
recognised that many neoplasms have multiple aetiologies. One may
also argue that,since the precise cause of most if not all neoplasms
is unknown,it is impossible to state with any certainty that a particular
type has only one definite aetiology.
support for an infectious origin of KS from the following data:-
1. The massive
increase in KS in AIDS patients-"at least 20,000 times more
common in persons with AIDS than in the general population and 300
times more common than in other immunosuppressed groups".
2. The fact
that "few known human carcinogens increase the risk by more
than 100 fold and,in the best documented example, hepatitis-B and
hepatoma,the cause of the cancer is an infection".
3. In immunosuppressed
subjects such neoplasms "may have an infectious cause"
However a high
incidence of a relatively rare disease in a confined population
does not necessarily indicate an infectious origin. Malignant mesotheliomas
are exceptionally rare in the general population,approximately one
case per million (21). However,in a study published in 1988 of a
cohort of individuals employed by the Australian Blue Asbestos Company
that operated in Wittenoom in Western Australia,there were 33 deaths
from mesothelioma recorded. Even though this study grossly underestimates
the incidence of mesothelioma,it still reveals a greater than 5000
fold risk of dying from this disease in these individuals (22).
Asbestos, a non-infectious agent,has been accepted as the major
causal factor in this condition. In another study of 2271 deaths
of insulation workers who came into regular contact with asbestos
the cause of death in 175 was mesothelioma,an incidence of 7706
in 100,000 (8%)(23). The risks quoted in these studies are considerably
higher (50 and 800 times) than that associated with hepatitis-B
refered to by Beral.
The data concerning
hepatitis-B virus (HBV) and hepatoma were taken by Beral et al from
a paper by Beasley et al (24). This paper describes a prospective
study of 22,707 male civil servants from Taiwan where it was found
that"the incidence of primary hepatocellular carcinoma (PHC)
among carriers of hepatitis-B surface antigen (HBsAg) was much higher
than among non-carriers (1,158/100,000 vs 5/100,000)". These
authors put forward the hypothesis that hepatitis-B virus has a
primary role in the aetiology of PHC, an hypothesis that so far
has not been conclusively proven. The authors themselves state "alternative
explanations of the very high relative risk among HBsAg carriers
are that HBV is a cofactor with another aetiological agent or is
simply a risk factor. Case control studies have repeatedly shown
that PHC does occur in HBsAg negative subjects. This finding can
be taken to mean either that HBV is not sufficient to cause PHC
or that there are several independent causes".
also refer to the geographical correlation between the amount of
aflatoxin in food and the incidence of PHC that occurs in Africa.
They postulate that a similar relationship may exist in Taiwan but
also point out that,due to the eclectic nature of the Chinese diet,there
are insurmountable difficulties in studying this particular factor.
In support of their argument Beral et al also refer to a review
paper published by Kinlen in 1982 (6). This paper is cited as showing
that the increase in KS in immunosuppressed patients is caused by
an infectious agent. However the substance of Kinlen's review is
the appreciable increased incidence of non-Hodgkins lymphomas,primary
hepatocellular carcinoma,melanoma and KS in immunosuppressed individuals.
2. To refute
the immune surveillance hypothesis of carcinogenesis by pointing
to the fact that these same individuals do not share an increased
incidence in the common epithelial neoplasms.
3. To argue,without
any convincing proof,a role for ultraviolet light in the skin cancers,HBV
in hepatocellular carcinoma,Ebstein-Barr virus (EBV) for lymphoma
and cytomegalic inclusion virus (CMV) for Kaposi's sarcoma.
4. To speculate
that antigenic stimulation or even the immunosuppressive agents
themselves may directly cause some of these neoplasms. Thus Beral
and her colleagues base their infectious theory of KS either on
an unproven hypothesis (HBV and hepatoma;lymphomas and EBV) or on
an hypothesis (CMV and KS) which they (and many others) consider
to be incorrect.
Beral and her
co-authors reported several interesting and relevant findings concerning
the incidence of KS in the various AIDS risk groups. Forty per cent
of homosexual and bisexual men in 1985 and approximately 21% in
1988 had KS compared with approximately 1% of haemophiliac AIDS
patients. The next highest incidence,6%,was from patients born in
the Carribean and African countries but living in the USA. There
were 73 cases of KS in transfusion recipients. KS was most unusual
in patients less than 15 years old,occuring in 1.6% of all children
with AIDS,(13 cases). All but one of these US born children with
KS were children of Haitian women, the other child was born in Central
America and raised in the United States.
were interpreted as evidence that:-
(i) KS is "caused
by an as yet unidentified sexually transmitted infection".
(ii) The appearance
of the agents in transfused patients older than 15 years "may
be by routes other than blood".
(iii) The agent
in children younger than 15 may be perinatally transmitted.
If the above
conclusions are correct then because:-
(i) There is
no cure for the disease;
(ii) In non
AIDS patients the disease is chronic,that is median survival is
have a higher frequency of all the sexually transmitted diseases
especially in Africa where treatment is not readily available; one
would expect a high incidence of KS in families (mother-child,husband-wife)
Africa where it was known as far back as 1962 (5) that "the
disease occurs not uncommonly in African children in the first decade
of life and is probably much underdiagnosed", the incidence
of KS in women (mothers) including prostitutes like elsewhere in
the world is low,with a male to female ratio of 17:1. Among the
many theories put forward before the AIDS era regarding aetiology
of KS,the two most often mentioned were infectious and genetic.
In order to test these theories many investigators searched for
a familial incidence of KS. A very small number of cases with a
familial distribution of KS were reported before the AIDS era but
in none of these were sexual or mother-child relationships involved
(25). Thus before AIDS there was no evidence to suggest that:
1. KS, at least
in heterosexuals, is sexually transmitted,
2. The cause
of KS is an infectious agent.
with the exception of CMV and HIV,which are still considered by
some as major aetiological factors,all the other factors considered
possibly pathogenic are non-infectious (2).
that in homosexual AIDS patients KS is caused by prolonged and repeated
exposure to semen,nitrites or both agents which,under normal circumstances,in
non-AIDS patients, are either absent or largely excluded from contact
with endothelial targets in the vascular or lymphatic system. Both
these agents are potent oxidising agents in biological systems (26,27)
and indeed oxidation is essential for many of their biological properties
and effects. For example,sperm maturation (and thus fertilisation)
is a process which requires the oxidation of sperm nuclear sulphydryl
groups to disulphides (28). All cells exhibit a thiol cycle and
this cycle is a principal determinant of many cellular functions
including mitotic rate (26). Thus nitrites and sperm, like all carcinogens
and mitogens,by their oxidative nature may induce perturbation of
the thiol cycle,and this effect may underlie the ample epidemiological
evidence that semen and nitrites are alone the two factors highly
correlated with the appearance of KS in homosexuals (29,30).
as a major property a prominent effect on vasculature. Although
the use of nitrites (poppers) is highly correlated with the appearance
of KS in homosexuals, their causative role has been dismissed because
of the belief that it is impossible to disentangle their use from
sexual practices and also because they do not explain "the
occurrence of KS in children and elderly people with parenterally
transmitted HIV and in one tenth of AIDS patients in Africa where
nitrites cannot account for the pattern of occurence of KS"
(20). The only reason for preferring the explanation that an "undefined"
infectious factor relating to sexual behaviour appears to be the
cause, and not the alternative,appears to be a predisposition to
favour a sexually transmitted infection. In fact in homosexuals
evidence exists that the variable most strongly associated with
KS is the consumption of more than four "hits" of nitrites
per night of use (30). The fact that the effects of nitrites and
sexual practices are "difficult to disentangle" does not
negate the possibility that nitrites acting alone or in combination
with another highly correlated variable may have a direct causal
role. While it may be true that Africans do not use nitrites,it
is also true that in Africans KS has existed independently of AIDS,
probably for centuries and, although not disproven,an infectious
origin of KS in Africa has been discounted as far back as 1962 (5).
The common diagnosis of KS in African patients post 1983 as AIDS
whilst "legal" (19) is a semantic convenience with little,
if any, scientific rationale,especially in relation to a putative
KS in children
that,in the thirteen AIDS children with KS,the cases of KS were
"atypical" and admits that "diagnostic biases might
exist". Also,because all children were from Florida where nitrite
abuse is most prevalent and all but one were offspring of women
born in Haiti,the possibility cannot be excluded that:
1. Some of
these children may not have developed KS.
of Haitian women,most of whom are descendents of African slaves,
may, like African children, have an appreciable incidence of KS
that has existed independently for many decades.
of these children may have used nitrites.
KS in recipients
of blood transfusion.
A total of
73 cases of transfusion associated KS have been reported by the
CDC up to March 31st 1989. In these patients not one
of their sexual partners had KS. According to the CDC definition
which "accepts HIV as the cause of AIDS" KS occuring in
anyone under the age of 60 years, even when laboratory evidence
regarding HIV infection was either not obtained or was inconclusive,
indicates AIDS. Individuals with KS who are over the age of sixty
and who have a positive antibody test are also considered AIDS patients.
KS which develops in persons who received high doses or long term
systemic corticosteroid or other immunosuppressive/cytotoxic therapy
but which were discontinued three months before the appearance of
the disease also indicates AIDS (19). In the United States,where
approximately 3. 8 million people are transfused annually,approximately
20% receive blood for treatment of malignant neoplasia (32).
data are unavailable it is certain that many of these patients will
have received varying combinations of immunosuppressive therapy,radiation
and chemotherapy,all agents known to be associated with the appearance
of KS (6). It is reasonable to question whether the occurence of
73 cases of transfusion associated KS over a period of eight years,
an average of 9 cases per year, represents a phenomenon peculiar
either to the specific practice of blood transfusion or to the AIDS
era. In the United States the annual incidence of KS in the general
population pre-AIDS is unknown but is estimated to be 0.2-0.6 cases
per million (4). There are no data available on the incidence of
KS in transfusion recipients pre-AIDS but these persons,50% of whom
die within one year of transfusion, are likely to have a higher
incidence than the general population.
of nine cases in nearly four million transfused therefore may not
be significantly higher than expected since many of the post 1981
transfused group would be expected to be under the age of sixty
years (and therefore fulfill the CDC AIDS definition), and/or suffering
from malignancy. There has also been a well documented problem in
establishing a definite diagnosis of KS in AIDS patients, a factor
which relates both to diagnostic bias and histopathological interpretation
(20,32). In the absence of data to prove the contrary the low incidence
of KS documented by Beral et al may simply reflect the presence,in
this population,of other causes of KS which have previously operated
and continue to operate independently of AIDS related factors. Also
in the United States there are 2.5 million exclusively homosexual
males, and perhaps another 2.5 to 7.5 million who may have the occasional
homosexual liaison (33). There are also at least 1.1 million IV
drug users,11% of whom use nitrites. Furthermore there are estimates
that 1% of American students between the ages of 12-17 years of
age use nitrites at least ten times per month (34). The CDC publically
accepts that this is likely to be an underestimate as not every
person questioned would feel comfortable admitting to drug abuse
or homosexuality. We may therefore argue that since KS even post
AIDS is so rarely reported in the non-homosexual non-drug abuser
population that some, if not all, of the blood transfusion-associated
KS cases may be related to one of the above mentioned mechanisms
which include chemotherapeutic agents,radiation,semen and nitrite
exposure-that is,to a cause which is not a sexually transmitted
infectious agent. Even if it is true that not a single African,child
or transfusion recipient is exposed to nitrites there is still no
compelling evidence to exclude nitrites as a cause of KS in homosexuals
since there is no proof that KS in all these groups is caused by
the one and the same factor. However in the case of homosexuals
with KS there is also other evidence which suggests that nitrites
may be aetiological agents:
1. One of the
only two factors which changed in the lifestyle of homosexuals in
the late 1970's was increasing nitrite abuse (35).
2. In the early
1980's nitrite use became ubiquitous in California and New York-the
two areas where the vast majority of patients with KS were found
3. The latency
period for the appearance of KS in patients treated with immunosuppressive
drugs for organ transplantation is similar to that between homosexual
exposure to nitrite and the appearance of the disease (36).
4. The decrease
in the incidence of KS in homosexual men coincided with a decrease
in nitrite abuse (37).
and their metabolic products are mitogenic and carcinogenic (36).
have major pharmacological effects on blood vessels-the site of
the neoplasm-which is an unusual tissue for neoplastic transformation
A second factor
directly relating to the development of KS is sexual intercourse.
While this may suggest that the disease at least in homosexuals
is caused by a sexually transmitted agent there are data available
from numerous large,well designed studies that strongly support
the hypothesis that semen itself has a direct causal role. All these
studies have shown that in homosexuals,the only sexual acts directly
related to both the developement of AIDS and Kaposi's sarcoma is
passive anal intercourse (30,39,40). One can surmise from these
data that if a large group of homosexuals could be studied where
any individual could be guaranteed to practise exclusively passive
or active intercourse and not both,then one would observe that:-
(i) KS,like pregnancy,can only be acquired by the passive partner.
(ii) KS,like pregnancy,cannot be sexually transmitted. As far as
the cause is concerned at least two possibilities can be entertained:-
1. In the passive
partner KS could be caused by an infectious agent found in the ejaculate
which is not bidirectionally sexually transmitted. The active partner
would have to acquire the agent by other means.
In the passive
partner KS could be caused by a non-infectious agent found in semen
acting either alone or synergistically with nitrites. That this
is the case is strongly supported by the following data:-
1. Apart from
nitrite abuse the second factor which changed in the lifestyle of
homosexuals in the mid 1970's was the high promiscuity rate (35).
There are also many examples from clinical practice of homosexual
men who admit to approximately one thousand partners per year. At
2-3 ml per ejaculate this provides evidence that deposition of unusually
large amounts of semen into the rectum of an individual can occur,and
that as a consequence,semen may interact with and be absorbed by
the intact or traumatised bowel.
2. Unlike all
the other sexually transmitted diseases,where the possibility of
infection is directly related to the number of sexual partners,in
homosexuals the number of sexual partners is only a risk in relation
to the number of episodes of passive anal intercourse (40).
have a relatively high incidence of gastrointestinal cancers other
then KS and several researchers have implicated semen in the developement
of these neoplasms (41,42).
4. Reid and
Coppelson described the relative high incidence of cervical cancers
in promiscuous Australian women. Amongst other factors,this was
attributed to semen (43).
penetration into the submucosa of the rat uterine epithelium can
induce pre-cancerous changes in the cervix (44).
6. In humans
spermatozoa fulfil a well known mitogenic role in embryogenesis.
There is also in vitro evidence that spermatozoa can penetrate somatic
mammalian cells and that sperm DNA is incorporated into recipient
occurs within a few days and this is associated with abnormalities
in morphology and growth of recipient cells including the appearance
of bi- and multi-nucleated cells (45,46).
of pooled human semen are potent promoters of skin tumour production
in the skin of mice previously treated with topical carcinogen (47).
of sperm suspensions directly into the anterior prostate of experimental
rats can produce carcinoma of the prostate with metastases (48).
injection of autologous spermatozoa in the rat can produce malignant
testicular neoplasms (49).
plasma is especially rich in polyamines, a group of positively charged
substances which have a significant role in cellular proliferation
(50,51). Moreover in human semen the polyamine spermine is present
in higher concentrations than in any other tissue or body fluid
and it, like other seminal polyamines, is oxidized by enzymes derived
from seminal vesicle secretion. The presence of polyamines in higher
than normal concentration in malignant tissue has prompted their
assay as a diagnostic aid in cancer patients and serial measurement
has been suggested as a treatment marker during chemotherapy. (Interestingly
it appears that polyamines are essential for optimal growth of most
microorganisms and inhibitors of their biosynthesis have been successfully
employed for the treatment of protozoal diseases including Pneumocystis
carinii pneumonia (52)).
Thus a mitogenic
and carcinogenic effect of nitrites and semen (or their derivatives)
may better account for the presently available epidemiological data
on KS in homosexuals than a currently unspecified,unknown new,sexually
transmitted infectious agent.
evidence that the oxidative effects of semen and/or nitrites play
a pivotal role in the development of KS in homosexual AIDS patients.
If anally deposited semen causes KS, we predict that case-controlled
studies should show that:-
1. In a group
of exclusively passive homosexuals who also use nitrites,cessation
of exposure to semen by the use of condoms should lead to a reduction
in the frequency of KS.
2. Women who
do not use drugs including nitrites but who practise anal intercourse
should have a higher incidence of KS than those who do not. If nitrites
play an aetiological role in the development of KS then future observation
will show that:-
1. In groups
of people who inhale nitrites and who have a high incidence of KS
the frequency should diminish when all other factors are kept the
same but nitrite inhalation is stopped.
2. In case
control studies where the test population is identical in all aspects
to the control population apart from inhaling high concentrations
of nitrites,a high frequency of KS should be seen in the test cases
but not in the controls.
If anally deposited
semen by itself cannot cause KS,but is an exacerbating factor when
nitrites are used, then case-controlled studies should show an excess
of KS in homosexuals who in addition to inhaling nitrites, practise
exclusive passive anal intercourse.
this theory predicts that reducing agents may prevent or even ameliorate
KS in homosexual AIDS patients. In this regard, the recent discovery
of significant reductions in cellular reduced glutathione in AIDS
patients lends strong support for contemplating such a therapeutic
We wish to
thank all our colleagues and especially Bruce Hedland-Thomas, David
Causer, Richard Fox, John Peacock, Rod Minchin, David Prentice,
Ronald Hirsch, Patricia Shalala, Keith Jones, Alun Dufty, June Rider
Jones, Coronary Barrow, Dorothy Davis Julian Smith and Wallace Turner
for their continued support and assistance.
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