Discussion

Dr. Safai: Dr. Abrams, I am not convinced that the apparent
drop in KS incidence is real. I see many referred patients who
have developed KS, but whose KS has never been reported, since
it was not the initial presentation of HIV infection. In many
cases, the lesions are not even biopsied.

Dr. Abrams: That is true, Dr. Safai, but it is still my
clinical impression that there were many more cases of KS earlier
in the epidemic. Since people develop KS while their CD4 counts
are still relatively high, I have always wondered whether that
might have been an earlier manifestation of immune deficiency,
plus the contribution of the KS cofactor. With safer sexual practices,
transmission of that cofactor could have declined so that people
do not develop KS until later in the progression of HIV. Clinically,
I feel that we are seeing fewer patients with KS, that those patients
have more advanced immune damage, and that their KS is more dangerous
than the indolent cases we used to see.

Dr. Safai: I am not disputing that there is a trend toward
decreasing incidence of KS. I just doubt that it is as steep as
these numbers seem to suggest. In many cases I have seen, if the
patient is relatively well and has only a few KS lesions, the
KS is not reported. My next question is, if nitrites cause KS,
why was there not more KS before the HIV epidemic?

Dr. Haverkos: Perhaps because the key element is some kind
of interaction between HIV and one or more cofactors. This is
a multifactorial tumor that probably requires both factors to
trigger whatever cellular mechanism is involved.

Dr. Abrams: Dr. Safai, I am interested in the question
of whether KS metastasizes. Early on, we realized that patients
with minimal KS who presented with their first episode of Pneumocystis
pneumonia would sometimes have increases in their KS lesions.
What do you think is happening in such cases?

Dr. Safai: I think that it is either a flare or a proliferation
of an existing tumor or the development of a new tumor at a different
site. This is not true metastasis, which means that the cell of
origin travels through the body, lodges in a new site, and begins
to proliferate. This does not happen in KS, and therefore it does
not metastasize in the same way that melanoma metastasizes.

Dr. Abrams: Perhaps an opportunistic infection adds further
insult to the immune system or increases cytokine production.

Dr. Safai: We would like to investigate that, Dr. Abrams,
but there are so many other infections in AIDS patients that sorting
out the cytokine picture is very difficult. Frankly, I suspect
that what is involved is not really immunosuppression, but immune
dysregulation, which allows the overproduction of cytokines that
cause the proliferation of the endothelial cell. Monocytes probably
also play a role, since they are capable of secreting cytokines
and are under the control of the immune system. Cytokine release
may increase in response either to iatrogenic immune suppression
or to amyl nitrite or some other factor. The ultimate question
is, what is the cytokine that drives the KS cell, and does it
go up or down when we block the immune system with prednisone
or cyclophosphamide?

Dr. Abrams: We have all feared that steroids would cause
the appearance or progression of KS in AIDS patients, but I cannot
remember seeing KS flares in patients on steroids for idiopathic
thrombocytopenia purpura or for respiratory compromise associated
with Pneumocystis pneumonia. Dr. Safai, is this really an issue
in our patients with HIV-related disease?

Dr. Safai: Probably not. In 20 years at Memorial Sloan-Kettering,
I saw very few cases of KS arising in patients treated with immunosuppressive
therapy. Furthermore, I have not seen or heard of any HIV-infected
person who developed KS after steroid treatment.

Dr. Abrams: One final comment with regard to the edema
you described. Our house staff has frequently worked up patients
who have unilateral lower extremity edema, but few KS lesions,
searching for deep-vein thrombosis or a pelvic mass, and these
cases are invariably negative. Unilateral edema, particularly
in the lower extremities, may appear much out of proportion to
the extent of KS lesions on the extremity.

Dr. Abrams, after your initial approach, when the patient develops
progressive KS lesions, what is your second-line therapy?

Dr. Abrams: Oral etoposide is a useful salvage therapy,
particularly since by the time the patient develops this kind
of progression, there are often venous access problems that make
an oral formulation desirable. There are problems with myelotoxicity,
however.

Dr. Safai: Dr. Abrams, we have had similar problems to
your's in developing a reproducible staging classification for
KS. To some extent, this probably just reflects some of the special
characteristics of this disease.

Dr. Abrams: It certainly hampers our ability to interpret
and compare data, Dr. Safai. Moving on to research on DaunoXome,
could you please explain, Dr. Chew, why, if the plasma area under
the curve is so high with DaunoXome and the half-life is so long,
there is so little toxicity?

Dr. Chew: Apparently because there is so little release
of free drug into the circulation. The plasma drug levels reflect
levels of the liposome-encapsulated drug. This translates into
more drug delivered to tumor cells and less delivered to myocardium,
hair follicles, bone marrow, gastrointestinal mucosa, and other
tissues.

Dr. Safai: Why do you think there is more tumor concentration
of this drug in the liposomal form than as free drug?

Dr. Chew: I believe there is probably active tumor endocytosis
of the liposomal particles, which then breaks down and releases
free daunorubicin inside the tumor cell.

Dr. Abrams: Dr. Gallo, your comments about gamma interferon's
role may explain some results we observed in an early trial. We
concluded that interferon-g was contributing to a more rapid decline
in our AIDS patients.

Dr. Gallo: In terms of KS, interferon-g appears to be the
most important of the inflammatory cytokines released by activated
T-cells. It is the most potent at inducing activated spindle cells,
so I would predict that giving exogenous interferon-g would make
matters worse for an HIV-infected patient.

Dr. Haverkos: I am interested in your suggestions about
inflammatory cyto-kine levels possibly being higher in homosexual
men than in intravenous drug users. However, we have been following
cohorts of homosexual men and, of injection drug users in several
cities, and we find very few differences in immunologic measures
of disease progression between these two groups.

Dr. Gallo: Intuitively, I am amazed at that, but it does
point out the need for more studies. As you know, assaying cytokines
is extremely difficult. The available assays are often less than
ideal, and turnover rates are very high. In addition, local production
of cytokines may be most important, which could be even more difficult
to measure. However, if this urine neopterin assay holds up, we
should start measuring it in the urine of homosexual men vs IVDUs.

Dr. Abrams: Dr. Gallo, what is your general feeling about
where AIDS research is going?

Dr. Gallo: I have the same "down" feeling many
researchers have with regard to progress in vaccine research and
to responding to the AIDS crisis in the developing world. I think
we are in desperate need of inspiration right now-not just AIDS
patients, but also AIDS researchers. However, I have just the
opposite feeling about the status of KS research. We are beginning
to really understand the underlying processes, and if researchers
and clinicians work closely together over the next year or two,
I think we will solve the problem of how to manage HIV-related
KS.