[PAGID] lymphopenia, Castleman's

Tue Jun 20 14:34:36 EDT 2006

Retinoids (differentiating agents), including 9-cis-retinoic acid and all
trans, are described as having activity against Kaposi's sarcoma. Kaposi's
sarcoma–associated herpesvirus (KSHV, human herpesvirus 8 HHV-8) is involved
in the development of body-cavity lymphomas, Kaposi's sarcoma, and
multicentric Castleman's disease.  They are certainly less toxic than
traditional chemo...

Andy Saxon, UCLA

Rieu P, Droz D, Gessain A, Grunfeld JP, Hermine O, Retinoic acid for
treatment of multicentric Castleman's disease. Lancet. 1999 Oct
9;354(9186):1262- 

A 35-year-old woman had been in excellent health until 1 month before
admission, when she developed progressive weakness, fever in the evening,
and oedema with weight gain. Physical examination on admission showed normal
blood pressure, multiple enlarged small peripheral lymph nodes,
hepatosplenomegaly, pleural effusion, and marked peripheral oedema. No
neuropathy or skin changes were noted. Investigation showed mild renal
insufficiency (creatinine=140 µmol/L) with proteinuria (0·7 g/d) and
microscopic haematuria. Blood count showed a normocytic anaemia (Hb=10 g/dL;
MCV=87 fL) without laboratory signs of haemolysis. Leucocyte and platelet
counts were normal. C-reactive protein was 53 mg/L. Plasma albumin and
globulin concentrations, serum immunoelectrophoresis, fibrinogen,
antinuclear antigen, serum complement, antiphospholipid antibodies, blood
culture, and viral serological tests (HBV, HCV, HIV-1) were normal or
negative. Biopsy of an axillary lymph node showed angiofollicular lymphoid
hyperplasia, consistent with Castleman's disease of the hyaline vascular
type. PCR analysis for HHV-8 sequences on lymph-node biopsy material was
negative. Renal biopsy showed lesions similar to those of thrombotic
microangiography. No immune deposits were identified by immunofluorescence.
In hospital, hypertension developed and was gradually controlled with the
use of three antihypertensive agents. Once blood pressure was controlled,
oral prednisone (0·5 mg/kg day) was started. After 2 weeks, fever, weakness,
oedema, peripheral lymphadenopathy, and splenomegaly persisted.
All-transretinoic acid treatment (45 mg/mbbib2 2 daily orally) was then
added to prenisone. This resulted in marked improvements in her symptoms
within a week. After 1 month of treatment, physical examination and
laboratory tests were normal. Prednisone was gradually reduced and
completely discontinued after 12 months. Retinoic acid was initially given
for 6 weeks, and thereafter for 14 days every 2 weeks for 9 months. After 1
year off treatment, she remains without symptoms and with normal laboratory
tests 

Retinoic acid have been recognised as an important immunoregulating agents.
It has potential therapeutic effects in diseases associated with
overproduction of interleukin-6 (IL-6) and endothelial injury such as
Kaposi's sarcoma and POEMS syndrome,bbib1 1 and bbib22 two diseases that
have been reported in the course of multicentric Castleman's disease.
Recently, Raife et al reported a patient with thrombotic thrombocytopenia
purpura (TTP), refractory to conventional therapy, who entered into
remission after 13-cis retinoic acid treatment.bbib3 3 It is noteworthy that
IL6 is raised in serum of children with TTP and that IL6 levels vary with
disease activity.bbib4 4 IL6 plays a central part in the pathophysiology of
Castleman's diseasebbib5 5 and vascular lesions are important features. The
response to retinoic acid and prednisone seen in this patient may therefore
result from modulation of IL-6/IL-6R autocrine/paracrine loop or a
beneficial effect on endothelial injury. 
  <http://www.sciencedirect.com/scidirimg/sci_dir/line.gif> 

bibl001bibl001
References

bib11 S Nagpal, J Cai and T Zheng et al., Retinoid antagonisms ofNF-IL6:
insight into the mechanism of antiproliferative effects of retinoids in
Kaposi's sarcoma, Mol Cell Biol 17 (1997), pp. 159–168. 

bib22 FJ Authier, L Belec and Y Levy et al., All-trans-retinoic acid in
POEMS syndrome. Therapeutic effect associated with decreased circulating
levels of proinflammatory cytokines, Arth Rheum 39 (1996), pp. 1423–1426.
Abstract-MEDLINE | Abstract-Elsevier BIOBASE   

bib33 TJ Raife, J McArthur, C Peters, CT Kisker and SR Lentz, Remission
after 13-cis retinoic acid in thrombotic thrombocytopenic purpura, Lancet
352 (1998), pp. 454–455. SummaryPlus | Full Text + Links | PDF
<http://www.sciencedirect.com/science?_ob=MiamiImageURL&_imagekey=B6T1B-4FWV
33M-1D2-1&_cdi=4886&_user=4423&_check=y&_orig=search&_coverDate=08%2F08%2F19
98&_qd=1&view=c&wchp=dGLbVlb-zSkWz&md5=895e805584c8fbbac129b1e77f17c5f7&ie=/
sdarticle.pdf> (27 K) 

bib44 D Karpman, A Andreasson, H Thysell, BS Kaplan and C Svanborg,
Cytokines in childhood hemolytic uremic syndrome and thrombotic
thrombocytopenic purpura, Ped Nephrol 9 (1995), pp. 694–699. Abstract-EMBASE
| Abstract-MEDLINE   |
<http://www.sciencedirect.com/science?_ob=RedirectURL&_method=outwardLink&_p
artnerName=3&_targetURL=http%3A%2F%2Fdx.doi.org%2F10.1007%2FBF00868714&_acct
=C000059605&_version=1&_userid=4423&md5=0f637722aac071c7ff4f39b262294069>
Full Text via CrossRef 

bib55 JT Beck, SM Hsu and J Wijdenes et al., Brief report: alleviation of
systemic manifestations of Castleman's disease by monoclonal
anti-interleukine-6 antibody, N Engl J Med 330 (1994), pp. 602–605.
Abstract-MEDLINE | Abstract

-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org]On Behalf Of Christine Seroogy
Sent: Tuesday, June 20, 2006 11:20 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [PAGID] lymphopenia

Colleagues, 

I have an update on the patient I presented last week and, again, welcome
opinions in terms of management.  The pathology on the GI mass is now
finalized as Castleman's disease.  Clinically, he does not fit into
unicentric or multicentric, but falls somewhere in between.  It is CD20
negative and he is HHV8 positive.  So my heme/onc colleagues are planning on
treatment with chemotherapy vs. rituximab (even with known CD20 negativity);
and are inclined toward rituximab therapy.  Given his underlying
uncharacterized cellular immunodeficiency the move to BMT is being
entertained after treatment of the Castleman's.  I don't think he has an
allogeneic match and would require MUD.  Flow for SAP was normal. HIV
testing has been negative.  I am wondering if any of you have seen
Castleman's in your immunodeficient patients and if so what the treatment
was and clinical course?  Thank you, Chris

On Jun 13, 2006, at 9:32 PM, K. Scott Baker wrote:

We have had 2 cases in the last couple of years, the first ended up having
XLP, the second we have been unable to molecularly characterize a defect, he
has a “CVID” phenotype.  Interestingly his lymphoma was metastatic Hodgkin’s
at age 4, which recurred.  He is being treated for the recurrence and then
going to allo-HCT.  The XLP had several recurrences of his NHL (mainly
abdominal primaries).  He received non-myeloablative MSD BMT 2 yrs ago and
has had no evidence of his disease (or xlp) since.  Are you planning on HCT
for your patient?

K. Scott Baker, MD, MS

Pediatric Blood and Marrow Transplant Program

University of Minnesota

420 Delaware St. SE, Mayo Bldg. Room D557

Mayo Mail Code 484

Minneapolis, MN 55455

612.625.4952  FAX 612.626.1434

baker084 at tc.umn.edu <mailto:baker084 at tc.umn.edu> 

  _____  

From: pagid-bounces at list.clinimmsoc.org
<mailto:pagid-bounces at list.clinimmsoc.org>  [
mailto:pagid-bounces at list.clinimmsoc.org
<mailto:pagid-bounces at list.clinimmsoc.org> ] On Behalf Of Christine Seroogy
Sent: Tuesday, June 13, 2006 1:51 PM
To: pagid at list.clinimmsoc.org <mailto:pagid at list.clinimmsoc.org> 
Cc: Kakumanu Sujani
Subject: [PAGID] lymphopenia

Dear Colleagues,

I would like to get your opinions about a 15y/o boy was admitted to our
hospital with a gastrointestinal lymphoma (further characterization
pending.) He was initially seen in the immunology clinic here at 4 years of
age because of severe primary VZV infection. Evaluation at that time
demonstrated lymphopenia--predominately CD4--and poor mitogen response. His
B cell numbers and function is normal (measured by titers to various vaccine
antigens); he has been persistently hypergammaglobulinemic (IgG 1000s and
IgA 400s). NK cell numbers by CD16/56 slightly diminished. HIV nonreactive.
He developed a Burkitt's lymphoma around age 10 and was successfully
treated, he has had refractory sinus disease and recurrent OM. No other
infectious history or autoimmune phenomenon. No relevant family history. I
welcome any thoughts on how to pursue a molecular diagnosis on this child or
hearing if you have seen similar cases. Thank you, Chris

Chris Seroogy, M.D.
Assistant Professor
Dept. of Pediatrics
Mail: H4/474 CSC, Mailstop 4108
Shipping: H4/431 CSC, Mailstop 4108
600 Highland Ave.
Madison, WI 53792
phone: 608- 263-2652
fax: 608-265-0164

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