Aima 2012-3

3 - 3
- 2012
3 (3)
ISSN: 1792-7110
Hodgkin
:
.
: A. ,
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- 2012
Hodgkin
.
Guest Editor
HELLENIC SOCIETY OF HAEMATOLOGY
The Journal
of the Hellenic Society of
HEMATOLOGY
HELLENIC SOCIETY OF HAEMATOLOGY
BOARD OF THE HELLENIC
SOCIETY OF HAEMATOLOGY

President:

Vice Presidents:

General Secretary:

Executive Secretary:

Treasurer:

Members:

Nikolaos Charchalakis
Dimitrios Karakassis
Ioanna Sakellari
Elissavet Grouzi
Ioannis Kakkas
Panagiotis Panagiotidis
Georgios Vassilopoulos
Konstantinos Tsatalas
Panagiotis Tsaftaridis
Panagiotis Tsirigotis

:
:

. :

. :

:

:

EDITOR
Photis N. Beris
Professor of Haematology
Medical School Geneva University, Switzerland
Modile: +41 79 957 5461
e-mail: photis.beris@unilabs.com

: +41 79 957 5461
e-mail: photis.beris@unilabs.com
Co-editors
Helen A. Papadaki
-o
A.
University of Crete School of Medicine
Head of Department of Haematology
University Hospital of Heraklion, Crete
el.: +30 2810 394629
Fax.: +30 2810 394632
e-mail: epapadak@med.uoc.gr

.: 2810 394629
Fax.: 2810 394632
e-mail: epapadak@med.uoc.gr
Konstantinos Tsatalas
University Haematology Clinic
University General Hospital of Alexandroupolis
E-mail: ktsatala@med.duth.gr

E-mail: ktsatala@med.duth.gr
ASSOCIATE editor
Theodoros P. Vassilakopoulos
Assistant Professor
Haematology Clinic
National and Kapodistrian University of Athens
PAST C0-EDITORS
Nicolaos C. Zoumbos
-o
.
: , 27, 115 23 , .: 210 7211806

- : Vita Congress - . , 4 & . , 11528 ,
.: 210.72.54.360, Fax: 210.72.54.363, E-mail: info@vitacongress.gr, http://www.vitacongress.gr
: med, . 380, 153 41 , .: +30210.6000643, Fax: +30 210 6002295, E-mail: techn@hol.gr
ii

: , ,
McMorran BJ, Wieczorski L, Drysdale KE et al. Platelet
factor 4 and Duffy antigen required for platelet killing
of Plasmodium falciparum. Science. 2012;338:1348-51.
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References
1. Leslie M. Beyond clotting: the powers of platelets. Science. 2010; 328:562-564.
2. Peyron F, Polack B, Lamotte D, et al. Plasmodium falciparum growth inhibition by human platelets in vitro. Parasitology. 1989; 99:317-322.
3. McMorran BJ, Marshall VM, de Graaf C, et al. Platelets
kill intraerythrocytic malarial parasites and mediate murvival to infection. Science. 2009; 323:797-800
4. McMorran BJ, Wieczorski L, Drysdale KE, et al. Platelet
factor 4 and Duffy antigen required for platelet killing of
Plasmodium falciparum. Science. 2012; 338:1348-1351.
Haema 2012; 3(3): ii-vi

:
: , ,
Schenk T, Chen WC, Gllner S, et al. Inhibition of the
LSD 1 (KDM 1A) demethylase reactivates the all-transretinoic acid differentiation pathway in acute myeloid
leukemia. Nat Med. 2012;18:605-611.

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References
1. Pollyea DA, Kohrt HE, Medeiros BC. Acute myeloid leukaemia in the elderly: a review. Br J Haematol. 2011;152:524542.
2. Glasow A, Barrett A, Petrie K, et al. DNA methylation-independent loss of RARA gene expression in acute myeloid
leukemia. Blood. 2008;111:2374-2377.
3. Berglund L, Bjorling E, Oksvold P, et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol Cell Proteomics. 2008;7:2019-2027.
4. Sigalotti L, Fratta E, Coral S, et al. Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and
clinical applications. J Cell Physiol. 2007;212:330-344.
5. Binda C, Valente S, Romanenghi M, et al. Biochemical,
structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and
LSD2. J Am Chem Soc. 2010;132:6827-6833.
iv
Ex vivo expansion
: ;
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Lechman RE, Gentner B, van Galen P, et al. Attenuation
of miR-126 Activity Expands HSC In Vivo without Exhaustion. Cell Stem Cell 2012; 11:799811.

500 .
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factor, Angopoietin-1, Pleiotrophin) (..
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,
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HSC.
2000 ex vivo
expansion HSC homeobox
B4 (HoxB4)
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microRNAs (miR). Lechman et al. ( 2012) Cell Stem
Cell miR-126 HSC (
)
- , in-vivo
in-vitro. miR-126 HSC in vitro.
miR-126neg/low HSC 10
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Nature, JAK .2 JAK2
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bcr-abl
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1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind,

placebo-controlled trial of ruxolitinib for myelofibrosis. N
Engl J Med. 2012; 366:799-807.
2. Koppikar P, Bhagwart , Kilpivaara O, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to
JAK2 inhibitor therapy. Nature. 2012; 489:155-159.
3. Gotlib J. The Hematologist. 2012; 9:11.

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Haema 2012; 3(3): vii
Vol. 3, No 3
July - September 2012
Hodgkin LYMPHOMA
Guest editor: T.P. Vassilakopoulos
CONTENTS
Preface.................................................................................................................................................................................................vii
Theodoros P. Vassilakopoulos

1.
Hodgkin lymphoma: histological features and classification ..................................................................................... 185

P. Korkolopoulou, G. Levidou, E. Patsouris
2.
Biology of Hodgkin Lymphoma ............................................................................................................................................. 190

S.G. Papageorgiou, V. Pappa, I. Dervenoulas
3.
Hodgkin Lymphoma: clinical and laboratory findings and staging procedures ................................................. 203
G.A. Pangalis, M. Moschogiannis, X. Giakoumi, P. Tsirkinidis, S. Sachanas
4.
Hodgkin Lymphoma: First line treatment and prognostic factors ............................................................................ 212
.P. Vassilakopoulos, G. Boutsikas, A. Sarris, M.K. Angelopoulou
5.
Principles of radiation therapy in Hodgkin lymphoma ................................................................................................. 231

. Georgakopoulos, E. Peponi, M. Trichas
6.
Treatment of relapsed/refractory Hodgkin lymphoma ................................................................................................ 239

M.K. Angelopoulou, P. Flevaris, T.P. Vassilakopoulos
7.
Biologic basis of novel therapeutic strategies in Hodgkin lymphoma .................................................................... 250

E. Drakos, G. Rassidakis
8.
Targeted therapy in Hodgkins lymphoma Clinical aspects ..................................................................................... 260

I. Kotsianidis, E. Spanoudakis, K. Tsatalas
9.
Allogeneic hematopoietic stem cell (allo-HSCT) transplantation in Hodgkin lymphoma ............................ 266
P. Kaloyannidis, P. Tsirigotis, I. Sakellari
10.
The role of 18FDG PET/CT in the evaluation of Hodgkin lymphoma ..................................................................... 275
Ph. Rondogianni, I. Apostolidis
11.
Long-term complications of treatment for Hodgkin lymphoma .............................................................................. 285

P. Roussou, S. Karakatsanis
12.
Nodular lymphocyte predominant Hodgkin lymphoma ............................................................................................. 298

F.N. Kontopidou, Th. Kanellopoulou
13.
Unusual clinical manifestations and complications of Hodgkin lymphoma ........................................................ 307
14.
Hodgkin lymphoma in specific subgroups of patients ................................................................................................. 321
15.
Brief guidelines for treatment and follow-up of patients with Hodgkin lymphoma ......................................... 328
A.S. Symeonides
. Pyrovolaki, M. Psillaki, H.E. Papadakis
Cover page: Activation of Nuclear factor- (NF-) in Hodgkin-Reed-Sternberg cells. (See article in Haema 2012, Vol. 3, page 193, by
Papageorgiou SG et al.)
3, 3
- 2012
Hodgkin
Guest Editor: ..
...........................................................................................................................................................................................vii
.

1.
- Hodgkin.................................................................................................185
, ,
2.
Hodgkin...............................................................................................................................................190
. , ,
3.
Hodgkin..........................................................203
. , , ,
,
4.
Hodgkin: ..................................................212
. , , , .
5.
Hodgkin..........................................................................................231
, ,
6.
Hodgkin..........................................................................239
. , , .
7.
Hodgkin............................................250
,
8.
Hodgkin ..................................................................260
, ,
9.
Hodgkin.....................................................................................................266
, ,
10.
Hodgkin............................................................275
,
11.
Hodgkin..................................................285
,
12.
Hodgkin ......................................................................298
. ,
13.
Hodgkin...........................................................................307
.
14.
Hodgkin ...............................................................................................................321
, , .
15.
Hodgkin.................328
: - (Nuclear factor-) HRS.

. (, 2012, 3, . 193)

2012

23

2013

Guest editors ,

Guest editor

Guest editor K.
A
- Hodgkin
, ,
: Hodgkin (HL) , HL, / .
(CD20, CD79a, PAX-5+) ,
pop-corn (BCL-6, CD45, OCT-2 BOB-1+, CD15- CD30-),
(CD4+, CD57+)
. , . (in situ
). 4 HL , , . Hodgkin
Reed-Sternberg (RS), (CD30+, CD15+ CD45- CD20-/+, PAX-5
+) .
, (lacunar
RS ). , EBV+, .
()
HL.
,
. ,
, . , .
Haema 2012; 3(3): 185-189 Copyright EAE
Hodgkin (HL)
: 1)
, 2)

, 3) Hodgkin
Reed-Sternberg (RS) ,
,
: , , ,
75, 11527, e-mail: glevidou@ yahoo.gr
, 4) 1.
HL, (5%) HL (95% ), /

, ,
1-3. 4 HL- , ,
- ,
. et al
186
Epstein-Barr (EBV), .
1-3
: ( ) ,

pop-corn (LP ),

.
: 5%
. 30-50 .
: ,
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: 1)
, LP , , , 2)
, 3)
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3) LP
4)

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in situ ,

4.
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CD20+, BCL-6+
(CD23+)4.
: LP
(CD20, CD79a, PAX-5), BCL-6, OCT-2
BOB-1 CD45 .

MA, J . , HL
PU.15.
, CD15 CD30 . CD4+/CD57+ T .
(PD-1, BCL-6).
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LP

(TCRBCL-like). TCRBCL
CD8+ TIA-1+ .
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: LP ( ) ,
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: (10 >90%)
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) (>60 ). (70%)
(20-25%), (5%)
(<1%). HIV .
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,

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. et al
188
, CD79a ,
PAX-5 (B cell activator protein/BSAP) 95% ,
9. IRF4/MUM-1
. ,
. (~10%)
OCT-2
-1. EBV EBNA-1 LMP-1 EBNA-26-8. EBV
(~75%)
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),
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odgkin

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HL,
.
Hodgkin lymphoma: histological features and classification

by Penelope Korkolopoulou, Georgia Levidou, Efstratios Patsouris
First Department of Pathology, Laiko Hospital, University of Athens, Medical School, Athens, Greece
ABSTRACT: Hodgkin lymphoma (HL) is classified into two major types, namely nodular lymphocytic predominance (NLPHL) and classical HL (CHL) which have distinct morphological, molecular and
clinical features. NLPHL is characterized by a nodular growth pattern and the presence of monoclonal
neoplastic pop-corn B cells (CD20, CD79a, PAX-5+) with a distinctive immunophenotype (BCL-6,
CD45, OCT-2 and BOB-1+, CD15- CD30-), within a network of dendritic cells rich in mature B and T
(CD4+, CD57+) lymphocytes. A variety of morphological subtypes have been described but without any
clinical relevance. Recent data suggest that NLPHL cases with micrornodular pattern, in which small
germinal centers (GCs) or broken up GCs are present, should be regarded as an early lesion limited to
the GCs (in situ lymphoma). CHL is further classified into four subtypes; nodular sclerosis, mixed
cellularity, lymphocyte-rich and lymphocyte-depleted classical HL. The hallmark of CHL is Hodgkin
and Reed-Sternberg (RS) cells, which bear a characteristic immunophenotype (CD30+, CD15+ CD45CD20-/+, PAX-5 faintly+) and are located within a polymorphous reactive cellular background. In particular, nodular sclerosing CHL is characterized by bands of fibrocollagenous tissue surrounding nodules
of inflammatory background cells containing Hodgkin and RS cells, often with a lacunar morphology.
In mixed cellularity CHL, Hodgkin and RS cells are mostly EBV+ and are scattered in a polymorphous
reactive background. According to the latest WHO classification, cases of CHL that cannot be otherwise
classified are placed into the mixed cellularity category. Lymphocyte-rich CHL has a nodular growth
pattern composed predominantly of small B lymphocytes containing atrophic, eccentrically placed GCs.
The RS cells are located within the nodules or in their expanded mantle zone but not outside them. Fi-
- Hodkgin
189
nally, lymphocyte-depleted CHL is characterized by the presence of many Hodgkin/RS cells and decreased number of lymphocytes.
1. WHO Classification of Tumours of the Haemopoietic and

Lymphoid tissues. Edited by Swerdlow SH et al, IARC,
Lyon 2008, pp: 321-334.
2. Schnitzer B. Hodgkin lymphoma. Hematol Oncol Clin North
Am. 2009; 23:747-768.
3. Anagnostopoulos I, Hansmann ML, Franssila K, et al. European Task Force on Lymphoma project on lymphocyte
predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of
Hodgkin disease with a nodular growth pattern and abundant
lymphocytes. Blood. 2000; 96:1889-1899.
4. Carbone A. Does in situ lymphoma occur as a distinct
step in the development of nodular lymphocyte-predominant
Hodgkin lymphoma? Cancer. 2012; 118:15-16.
5. Torlakovic E, Tierens A, Dang HD, Delabie J. The transcription factor PU.1, necessary for B-cell development is
expressed in lymphocyte predominance, but not classical
Hodgkins disease. Am J Pathol. 2001; 159:1807-1814.

6. Delsol G, Brousset P, Chittal S, Rigal-Huguet F. Correlation
of the expression of Epstein-Barr virus latent membrane
protein and in situ hybridization with biotinylated BamHI-W
probes in Hodgkins disease. Am J Pathol. 1992; 140:247-253.
7. Hummel M, Anagnostopoulos I, Dallenbach F, Korbjuhn P,
Dimmler C, Stein H. EBV infection patterns in Hodgkins
disease and normal lymphoid tissue: expression and cellular
localization of EBV gene products. Br J Haematol. 1992;
82:689-694.
8. Weiss LM. Epstein-Barr virus and Hodgkins disease. Curr
Oncol Rep. 2000; 2:199-204.
9. Ehlers A, Oker E, Bentink S, Lenze D, Stein H, Hummel M.
Histone acetylation and DNA demethylation of B cells result
in a Hodgkin-like phenotype. Leukemia. 2008; 22:835-841.
10. Glaser SL, Clarke CA, Gulley ML, et al. Population-based
patterns of human immunodeficiency virus-related Hodgkin
lymphoma in the Greater San Francisco Bay Area, 19881998. Cancer. 2003; 98:300-309.
A
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T.: 210-5831663, Fax: 210-5831690, E-mail: sotirispapageorgiou@
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ID2
(natural killer, NK) , -
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192
1. HRS.

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- , -
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, .

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25. NF- -
(c-FLIP), () (.. BCL-XL, c-IAPs, Survivin, XIAP). c-FLIP,
Hodgkin
193
2. - (Nuclear factor-B) HRS.

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D2)
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: i) NF-,
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, TNF)
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-,

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EBV. 30-40% HL,
HRS EBV LMP1, CD40 NF-33,
iii) HRS. (genomic
gains) Rel, ( NF) NF-
NIK 40% 20% 34-35
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NFKBIE ( I) 1020% 36-38. , -
.. et al
194
1. HL, .

NF-B
CD40, CD30, TNF, RANK

LMP1 (30-40%)

REL* (40%)
* (20%)
NFKBIA** (20%)
NFKBIE** (15%)
TNFAIP3** (40%, 70% EBV-)
BCL3** (10%)
-
-
-
JAK-STAT
IL-13 & IL-13R (STAT6)

IL-21 &IL-21R (STAT5)

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SOCS1**
-
-
MAPK
CD40, CD30, RANK
PI3K/AKT/ mTOR
CD40, CD30, RANK

HSP90
-
- .
-
RTKs

- (PDGFRA, EPHB1)
- (DDR2, TRKA)
* (Gain or Amplification), ** (Point mutations) (Deletions)

TNFAIP3, 20 NF-,
40% 39,40,
HL40.
EBV, TNFAIP3 70% EBV- 40.
HL
NF- (.. NFKBIA TNFAIP3
2) ,
29,37,40-41. ,
42, NF- HL.
NLP-HL LP
NF-43. ,
,
NLPHL44.

AP-1 Hodgkin
HL AP-1,

JUN (c-Jun, Jun-B,
Jun-D), FOS (c-FOS, FOS-B, FRA-1, FRA-2)
ATF. AP-1,
stress
, ,
D1 p5345,46. AP-1 HL
Hodgkin
AP-1, c-JUN JUN-B47-49.

HRS AP-1 . P-1
NFB, D2,
c-met CCR7 ( homing ),
HRS. o Jun-B CD30 HL50.
NLP-HL, CD30,
AP-1
c-Jun Jun-B47,49. , AP-1 HL
.

HL
(Galectin, Gal) 51-53.
Gal-1 ,
-, 52.
HRS AP-1. Gal-1 HRS (>90%)
AP-1, c-Jun53. A, Gal-1 B-,
NLPHL, Gal-1 c-Jun 54.

HL

( 1).
JAK-STAT
.
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Biology of Hodgkin Lymphoma

by Sotirios G. Papageorgiou, Vasiliki Pappa, Ioannis Dervenoulas
Second Department of Internal Medicine, Propaedeutic, Hematology Unit, University of Athens,
University General Hospital Attikon
Abstract: Hodgkin lymphoma (HL) is a neoplasm of lymphoid tissue, derived from mature B cells
of germinal center and subdivided into classical and nodular lymphocyte predominant HL (NLPHL). HL
is unique among human B cell neoplasms due to the rarity of the malignant cells, the Hodgkin and ReedSternberg (HRS) cells in classical HL and the lymphocyte-predominant (LP) cells in NLPHL, which usually account for less than 1% of the cells in the affected tissues. Moreover, HRS cells are unique in the
Hodgkin
199
extent to which they show an abnormal reprogramming of B lymphocytic differentiation. This causes
an abnormal and complex immunophenotype that is characterized by the expression of a wide range of
antigens that are normally expressed by several distinct cell types. Deregulation of cell signaling pathways and transcription factors plays a key role in HL pathogenesis. Finally, HRS cells are found within a mixed reactive non-malignant cellular environment and interact with these nonmalignant cells in a
complex fashion that appears to be essential for HRS cell survival and proliferation.
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3%
,
,
<2%
<2%
: , .. , 619. , 2008
()
- ,
. -,
10% .
-,
,
. ,
.6,7 , ,
, .8,9
, ,
, . ( )
, ,
. , .
,
, . ,
,
, ,
(),

. , ,
, .
,
5% .10

HL, . , ,
, .

,
,
. (5-7%).11
O <10%
, (
, , )
205
20% . ( ) HL (/
), ,
30% .12,13
,
(
), .
Waldeyer, , L ,
-Hodgkin ,
( 2).

HL 3.

,
HL
, ,
.
, , -
2. Hodgkin -Hodgkin
Hodgkin
- Hodgkin

(- >80%, 50%,
- 40%, -: )

Waldeyer, ,
Waldeyer, ,

~20-30%

-Hodgkin

,

,
(
): ,
, , ..
: , .. , , 2008 ()
.. et al
206
3.
Hodgkin

(%)
(
)

80
Waldeyer
1

50

25
*
25
**
9

2

1

15
/
10
7

6
3

<1
* 30-40% .
** 30-35%
.
: , .. , 620. , 2008
().

. ,
.

HL , ,
.
L, 4.
. ,
,
. : , 50 mm/h
45% 100mm/h 15%
- .
C- (CRP),
60 (300 mg/L) 14. CRP,
98%
15, CRP 2
14.
4. Hodgkin
,
, , , V

(%)
*
16
60
9
34
54
(1010 /)
8
19
(<1109/)
28
40
(<1.5109/)
5
11
(0.7109/)
19
42
(>400109/)
50
23
68
100
3
29
LDH
15
34

8
19
(<3.5 gr/dl)
9
33
23
49
2 (>2.4mg/I)

37
44
13
34
8
28
44
15
23
12
22
34
**A <13gr/dl <11.5gr/dl .

: AIMA . .. , 621. , 2008 ()
207
CRP (, , ..) 15,17.

.
(
)
LDH 2-.18 , -GT ,
. ,
, .
()

HL . , ,
.
6% ,
, , ,
7-8%. -,
V , 35 , ( <13g/dl <11.5g/dl), (<6109/l)
/
.19 ,
, ,
Reed-Sternberg, Hodgkin, CD30. , .
HL
, .

50% ,
( )
( 1, ). ,
. ,
,
1,.
Hodgkin .
( ).
(
5-6).
0.33 ( 0.35 ),

0.45, .

HL
(CT) (), , -
208
,

.

. CT , /
( 2, , , ). CT,
.
.. et al
berg) 0.1-10% ,

( 3).
PET
(
, interim, ). , PET
L
, PET
, -

.

.

(MRI)
HL .
,

PET Scan (Positron Emission Tomography)

(PET), HL . PET /
, , PET CT.
(18FDG) ,

. HL,
( Hodgkin Reed Stern-
3.
Hodgkin .
.
2, , , . HL. (,), (), ().
()20,21

.
HL .
,

,
HL
80 90, PET.22
.

HL
, , , ( 5).
.

,
209

. 1975-1985
. ,
Ann-Arbor ( Michigan
, 1971
), Cotswolds (
)23 1989. HL,
, (, , , V)
6.
L . , .
, -
.
, . HL,

, , -
5. ,
Hodgkin
A.
.
.
-

-
(FDG PET-scan)

, ,
sAg, anti-HCV, anti-HIV

(F+P)

,

: . .. , 627. , 2008 ()
.. et al
210
6. Hodgkin. Ann-Arbor/ Cotswolds

(, , ..)
[]

[].

[.. 2].
,
.
3
,
[S],
[] [SE].
1: / /

2: ,
, (>380C) /
/ >10%
,
( >1/3
5/6 / 10)
* V.
**H (
) . .
*** (
).
: . . . , 626. , 2008 ()
.
,
, - .
Hodgkin Lymphoma: clinical and laboratory findings and staging procedures

by Gerasimos . Pangalis1,2, aria Moschogiannis1, Xanthi Giakoumi1,
Pantelis sirkinidis1,3, Sotirios Sachanas1
Department of Haematology, Athens Medical Center, Psychikon Branch, 2Department of
Haematology, National and Kapodistrian University of Athens, 3Department of Haematology,
401 General Army Hospital, Athens, Greece
1
Abstract: Hodgkin lymphoma usually affects young adults. The majority of patients present with
asymptomatic, non-tender, hard and fixed lymphadenopathy of the cervical, supraclavicular and/or ax-
211
illary areas. The disease commonly involves the upper mediastinum in the form of bulky lymphadenopathy. 30-40% of the patients, mostly with advanced stage disease, develop B-symptoms, which include
fever (usually >38C) which frequently has a cyclical high-grade character, drenching nights sweats and
weight loss (10% of the body weight in 6 months). Pain in the affected areas after consumption of alcoholic drinks is a rare but specific disease characteristic. Cervical and supraclavicular lymph nodes are
most commonly affected, followed by mediastinal, paraortic and axillary lymph nodes, while spleen involvement is reported in 20% of patients. The disease is rarely pure infradiaphragmatic while lung, bone
marrow and liver involvement are the commonest extranodal sites of disease. Laboratory findings are
usually normal, especially at early disease stage, whereas advanced disease is commonly accompanied
by anemia, leukocytosis with neutrophilia, lymphocytopenia and thrombocytosis. More than 50% of patients present with elevated ESR, while increased LDH, 2-microglobulin, a2 globulins and acute phase
proteins are observed in various percentages of patients. Staging procedures include plain chest X-rays
and whole body computed tomographies. FDG PET CT scan contributes to the evaluation of disease sites
undetectable by conventional imaging techniques as well as residual masses. Bone marrow trephine biopsy is necessary. The disease stage constitutes an important prognostic factor.
1. Grufferman S, Delzell E. Epidemiology of Hodgkins disease.

Epidemiol Rev. 1984; 6:76-106.
2. Glaser SL, Lin RJ, Stewart SL, et al. Epstein-Barr virus associated Hodgkins disease: epidemiologic characteristics in
international data. Int J Cancer. 1997; 70:375-382.
3. Jarrett RF. Viruses and Hodgkins Lymphoma. Ann Oncol.
2002; 13:23-29.
4. Pel P.K. Zur Symptomatologie der sogenannten Pseudoleukaniie. II Pseudoleukamie oder chronisches Riickfallsfieber?
Berlin Klin. Wchnschr. 1887; 24:644-646.
5. Epstein W. von. Das chronische Rckfallsfieber, eine neue
Infektionskrankheit. Berliner klinische Wochenschrift. 1887;
24: 565-568.
6. Connors JM. Clinical manifestations and natural history of
Hodgkins lymphoma. Cancer J. 2009; 15:124-128.
7. Barber NA, Bierman PJ. Recognizing unusual manifestations of Hodgkin lymphoma. Curr Hematol Malig Rep.
2012; 7:186-192.
8. Bichel J. The alcohol-intolerance syndrome in Hodgkins
disease. Acta Med Scand. 1959; 164:105-112.
9. James AH. Hodgkins disease with and without alcoholinduced pain. A clinical and histological comparison. Q J
Med. 1960; 29:47-66.
10. Pangalis GA, Vassilakopoulos TP, Boussiotis VA, et al.
Clinical approach to lymphadenopathy. Semin Oncol. 1993;
20:570-582.
11. Vassilakopoulos TP, Angelopoulou MK, Siakantaris MP, et
al. Pure infradiaphragmatic Hodgkins lymphoma. Clinical
features, prognostic factor and comparison with supradiaphragmatic disease. Haematologica. 2006; 91:32-39.
12. Cannon WB, Nelsen TS. Staging of Hodgkins disease: a
surgical perspective Am J Surg. 1976; 132:224-230.
13. Multani PS, Grossbard ML. Staging laparotomy in the
management of Hodgkins disease: Is it still necessary? The
Oncologist. 1996; 1:41-55.
14. Pappi V, Angelopoulou M, Tsopra O, et al. Baseline serum
C-reactive protein levels (CRP) in Hodgkin lymphoma (HL)
and alterations during ABVD chemotherapy: Correlation

with clinical, laboratory features and prognostic significance.
Haematologica/The Hematology J. 2010; 95(Suppl 2): 887.
15. , , .
(PCT)
Hodgkin (HL) /
C- (CRP) o.
- 23 , 22-24
2012, . . 2012; 3(4):125.
16. Koliaraki V, Marinou M, Vassilakopoulos TP, et al. A novel
immunological assay for hepcidin quantification in human
serum. PLoS One. 2009; e4581.
17. Vassilakopoulos TP, Nadali G, Angelopoulou MK, et al.
The prognostic significance of beta(2)-microglobulin in
patients with Hodgkins lymphoma. Haematologica. 2002;
87:701-708.
18. Vassilakopoulos TP, Pangalis GA. Biological prognostic
factors in Hodgkins lymphoma. Haema. 2004; 7:147-164.
19. Vassilakopoulos TP, Angelopoulou MK, Constantinou N,
et al. Development and validation of a clinical prediction
rule for bone marrow involvement in patients with Hodgkin
lymphoma. Blood. 2005; 105:1875-1880.
20. Schaefer NG, Taverna C, Strobel K, et al. Hodgkin disease:
diagnostic value of FDG PET/CT after first-line therapy-is
biopsy of FDG-avid lesions still needed? Radiology. 2007;
244:257-262.
21. Hutchings M, Eigtved AI, Specht L. FDG-PET in the clinical management of Hodgkin lymphoma. Crit Rev Oncol
Hematol. 2004; 52:19-32.
22. Friedberg JW, Fischman A, Neuberg D, et al. FDG-PET is
superior to gallium scintigraphy in staging and more sensitive
in the follow-up of patients with de novo Hodgkin lymphoma:
a blinded comparison. Leuk Lymphoma. 2004; 45:85- 92.
23. Lister TA, Crowther D, Sutcliffe SB, et al. Reports of a
committee convened to discuss the evaluation and staging
of patients with Hodgkins disease: Cotswolds meeting. J
Clin Oncol. 1989; 7:1630-1636.
A
Hodgkin:

. , , , .
: Hodgkin (HL) . , , Ann Arbor
( , -
,
). (/ ) 2-4 ABVD 20-30 Gy,
(/ 1 ) 4-6 ABVD
30 Gy. .
(III/IV /
), BEACOPP-escalated ABVD 60 , . 6 8
BEACOPP-escalated . , ABVD PET 2
BEACOPP-escalated
. PET ,
BEACOPP-escalated, 10% .
PET ABVD. ,
(IPS).
, . ,
HL
.
Hodgkin (HL)
, ... ,
,
: . ,
. ,
, ... , , .
17, , .. 115 27, , .: 210 7456902, Fax: 210
7456698, e-mail: theopvass@hotmail.com
2.4
100.000 . - .
(WHO)
: HL (cHL, 95%
)
(NLPHL, 5% ).

cHL, NLPHL .
Hodgkin:
HL ,
.

, ,
.
() ()
.

, -

.
1-13
(Ann Arbor
Cotswolds)1,2
, HL
. ( ) (
) ( 1).

, /
IV .
, 1 ,
,
Hodgkin (German Hodgkin Study Group-GHSG)
EORTC (European Organization for the Research
and Treatment of Cancer).
GHSG EORTC,

1 (+ 50 + 30, 3 4
, 50 ) ( 1).

GHSG EORTC ( 1).
3. ,

, 2 3-5
(.. / )6
.

,
( 2)6,8,9,11-13. ,
, GHSG
,
( )
1. Hodgkin

213
GHSG
EORTC
. 3
. 4
. A + 50 B + 30
. A + 50 B + 30
. *
. **
. -
. 50

I, II ..
I, II ..
I, IIA & 1 ..
I, II & 1 ..
IIB & .. /
IIB & .. /
III, IV
III, IV
* GHSG: 1/3 (0.33) ,

** EORTC: 0.35 5-6
..= , E-=
.. et al
214
2. GHSG EORTC ;
,
FFTF (%)
5-
8-
~90
~87
HD79
2 x ABVD + (30+10) Gy -
HD1012
2 x ABVD + 30 Gy -
86
HD10
4 x ABVD + 30 Gy -
~93
87
12
HD14 *
**
4 x ABVD + 30 Gy -
91
HD1113
4 x ABVD + 30 Gy -
85
~83
HD146*
4 x ABVD + 30 Gy -
89
HD14
4 x ABVD + 30 Gy -
88
H7F
6 x EBVP + -
88
H7U11
( )
6 x EBVP + -
68
H8F8
3 x MOPP/ABV + -
98
93
H8U8
( )
4 x MOPP/ABV + -
88
80
11
HD14 (16-60 16-75 HD10, HD11).

H8U EORTC .
* HD14 Progression Free Survival (PFS)
** 3 -
/ ( 3 -)
7F, H7U, H8F, H8U 10- 8-

FFTF= Freedom From Treatment Failure, = , = , = , =
(.. ~90%)
6. , EORTC ,
,
8,11.
(International Prognostic
score; IPS)7. ,
,
.
8-45
HL
(+).
+
,
,
, (Freedom From treatment
Failure; FFTF)8-11. ABVD (, , -
, ). ,
,
BEACOPP
ABVD ,
, ,

(PET-Scan).

4 ABVD

HL, 2 . 7.5 , HD10 GHSG
4 2 ABVD12
8- FFTF 88% 86% 8-
94.5% (
Hodgkin:
215
3. Hodgkin 6,8,12,13,17,27
-
HD10, GHSG12,
ABVDx2 + - 30 Gy
ABVDx2 + - 20 Gy
ABVDx4 + - 30 Gy
ABVDx4 + - 20 Gy
HD13, GHSG,
ABVDx2 + - 30 Gy
ABV x2 + - 30 Gy
AVD x2 + - 30 Gy
AV x2 + - 30 Gy
H8F, EORTC/GELA8,
MOPP/ABVx3 + - 36-40 Gy

+
H9F, EORTC/GELA27,
EBVPx6 + - 36 Gy
EBVPx6 + - 20 Gy
EBVPx6
HD11, GHSG13,
ABVDx4 + - 30 Gy
ABVDx4 + - 20 Gy
BEACOPP-basex4 + - 30 Gy
(FFTF)
FFTF, %
8
: 1190
295
86
4 vs 2 :
16-75 , 1998-2003
299
86
88% vs 86%, HR 1.17 (0.82-1.67)
: 91
298
87
30 vs 20 Gy:
298
90
88% vs 89%, HR 1.00 (0.68-1.47)
ABV
AV

: 542
15-70 , 1993-1999
: 92
: 578
15-70 , 2004
: 60
239
209
130
: 1395
16-75 , 1998-2003
: 91
356
347
341
5
89%
85%
69%
5
85
81
87
351
87
: 1528
18-60 , 2003-2008
: 43
765
763
5
88%
95%
: 996
15-70 , 1993-1999
: 92
336
333
327
10
82%
80%
80%
: 808
15-70 , 2002
: 67
276
277
255
5
91%
85%
89%
BEACOPP-basex4 + - 20 Gy
HD14, GHSG6,
ABVDx4 + - 30 Gy
BEACOPP-esc x2 + ABVDx2
+ - 30 Gy
H8U, EORTC/GELA8,
MOPP/ABVx4 +
K
H9U, EORTC/GELA17,
ABVDx6 + - 36-40 Gy
ABVDx4 + - 36-40 Gy
BEACOPP-basex4 + - 36-40 Gy
270
272
10
93%
68%
p<0.001
36 Gy vs. 20 Gy vs. RT: p<0.001

36 Gy vs. 20 Gy: p=0.19
RT
BEACOPP vs ABVD (30Gy): p=0.65
BEACOPP vs ABVD (20Gy): p=0.02
30 vs 20 Gy (BEACOPP):
-0.8% (-5.8 4.2)
30 vs 20 Gy (ABVD): -4.7%
(-10.3 0.8)
BEACOPP-esc vs ABVD: p<0.001
HR 0.44 (0.30-0.66)
p=0.80
p=0.27
,
HR = Hazard ratio
10 97% 92% (p=0.001) -
EBVP CR/CRu
.. et al
216
3). , 2 ABVD . , , EORTC

3 ABVD (www.clinicaltrials.gov, EORTC H10
trial) 3-4 14,15.
H8F EORTC 3
MOPP/ABV ()
10- FFTF 93% 10- 97%8.
MOPP
, .

GHSG EORTC,
HL
4 COPP/
ABVD MOPP/ABV -8,16. 80% ,
, ABVD,
.
6
4: 8U
EORTC MOPP/ABV
x 4 + -, MOPP/ABV x 6 + - MOPP/
ABV 4 8.
H9U EORTC
ABVD. . 5- FFTF 91% ABVDx6+-
85% ABVD x4+-,
,
17.
ABVD
HL 18,19, 4 ABVD
,
(standard arm)
HD11, HD14 H9U.
GHSG EORTC,
6 ABVD
, 20-24.
6 ABVD
-
HL. ,
, ..
-
1-2 -
,
6,25.
(
)
.

ABVD

HL. ,
.

HD13 GHSG, 2 ABVD 30 Gy -,
, .
ABV AV /.
( AVD) ,

ABVD ( ).

HD11 GHSG, 4
ABVD K- FFTF
4 BEACOPPbaseline K-, 30 Gy13.
, H9U EORTC
BEACOPP-baseline ABVD
17.
, HD14 GHSG FFTF (
) ABVD x 4 + 30 Gy
- 2 BEACOPP escalated BVD
x 2 + 30 Gy -6.

, . / .
. -
Hodgkin:

BEACOPP-escalated, .

-
HL ABVD ,
8,15,16. .

(involved node radiotherapy).
-
.

HL
30 Gy
, 36-45 Gy.
. - (32 Gy) (CR), (CRu)
(VGPR) 4-6 ABVD
EBVD (E=) 1988. 235
/3
276 26
28-32 Gy
<28Gy (
20-28 Gy).

,
.
HD10 GHSG
, ABVD x 2, 30 20 Gy
12. , H9F EORTC
, 5- FFTF 36 Gy 20 Gy - CR/
CRu 6 EBVP 89% 85% (p=0.19), 5-
100% 98% (p=0.41)27.
, ABVD x 4,
HD11 GHSG 5- FFTF 30
Gy 20 Gy - (85% 81%). , -
217
FFTF,
, . BEACOPP-baseline x 4.

13.
-
ABVD 30 Gy, 20 Gy ( 3).
;

.
,
(5 .)
PET/CT ,
VEBEP28-31.
. H9F EORTC

, , EBVP ABVD27.
-,
FFTF ,

32.
33 34-38
HL
NCIC/ECOG
HD.633. /

, 399 / ( )
(1 :
TKE 50, 4 ,
, 40).
, ABVD .
(STNI) 35 Gy ABVD x
2 + STNI 35 Gy .
:
ABVD x 2, CR/
CRu 2 ( 4),
(PR) 4 -
.. et al
218
( 6).
12- , .
ABVD
FFTF , 4.
. 12 24 :
,
(10 4). ,
8 (3 5 4 )
ABVD!

,
: (1) 35 Gy STNI
,
( -)
( 20-30 Gy)

, (2) 2 ABVD ( ) ( 4
), STNI
, (3)
8 ,
12 16
. -
, ~85%
, .
PET-Scan .
PET-Scan
O , PET-Scan
/39.
, PET-scan
, ,
5%
5 14,40-42. PET-scan
,
,
20-30%40 2-3
43. PET-scan ,
. 30 Gy -
(~40 Gy)
PET.
-
4. 12- NCIC/ECOG HD.633
12-
(n)
OS:
FFP:
EFS:
(n)
OS:
FFP:
EFS:
(n)
OS:
FFP:
EFS:
ABVD
ABVD
196
94%
87%
85%
59
98%
89%
89%
137
92%
86%
83%
203
87%
92%
80%
64
98%
87%
86%
139
81%
94%
78%
Hazard Ratio
(95% CI) ABVD /
ABVD
0.50 (0.25-0.99)
1.91 (0.99-3.69)
0.88 (0.54-1.43)
0.04
0.05
0.60
1.09 (0.07-17.40)
0.88 (0.31-2.55)
0.78 (0.28-2.19)
0.95
0.82
0.64
0.47 (0.23-0.97)
3.23 (1.28-8.13)
0.91 (0.52-1.59)
0.04
0.006
0.74
Hodgkin:
(
) .

HL
, PET/CT(-)
2 3 ABVD. PET
(. 10-12 . 15 2 3
ABVD) PET,

.
EORTC H10 ,

/ PET(-) 2 ABVD:
: (1) 1 2
ABVD ( ) 30 Gy ( ) (2) 2 4
ABVD ( )
( ). , (futility analysis)
2
, (ABVD )44.
,
RAPID14
- IA/IIA (<0.33
5/6), PET/CT(-) 1012 3 ABVD:
( Deauville 1 2 PET 10, 1)
- .
3- FFTF 93.8% vs. 90.7% .
-2.9% 95% -10.7% +1.4%.
(non-inferiority)
-7%, . 7%
. 2
.

EORTC H10
.
, PET
. , HD16 GHSG,
PET
ABVD. , H10 (F U) EORTC,
PET .
219
(interim) PET-Scan, 163 / 2- FFTF 94%

PET-Scan 2
ABVD 58% PETScan45. , ,
( ),
PET-Scan , .

/
PET-Scan
2-3 ABVD. , , PET-Scan
.

7,18-24,41-43,46-68
, ABVD,
HL,
. 60-70% ABVD,
BEACOPP-escalated.
CR/CRu

46-49. 3 ,

, .
PET/CT
.

HL . /V
19,50-53. : EORTC, GELA
HL19,51-53.
GHSG
HL, / 50. , -
220
,
20,21,23,24,54,55.
55-57
/ .
HL

MOPP 20- FFTF 30%
/V (
GALGB)18. ABVD
MOPP, FFTF. , 20- FFTF ABVD 40-45%.

, FFTF.

. , , 15 ABVD
60-65% (
2012). MOPP ( COPP)
ABVD 7 (MOPP/ABV) 10 (MOPP/EBV/CAD COPP/ABV/IMEP)
18-21,23,58,59.
, ChlVPP/
PABlOE ChlVPP/EVA ,
ABVD55.
, Stanford V ABVD,
,
21,56,57.
ABVD (gold standard)
HL,
.
1990, GHSG BEACOPP-escalated (BEACOPPesc),
7
. BEACOPPesc FFTF ABVD,

COPP/ABVD, ABVD50.
BEACOPPesc GHSG HL.
HD9, BEACOPPesc
.. et al
FFTF COPP/ABVD - ABVD- BEACOPP-baseline,

BEACOPPesc50.
HD960 10- FFTF
82%, 70% 64% BEACOPPesc, BEACOPPbaseline COPP/ABVD , 10- 86%, 80%
75%. , BEACOPP-baseline ,
COPP/
ABVD. BEACOPPesc
COPP/ABVD FFTF
IPS, IPS 2-3.
IPS.
,
BEACOPPesc COPP/ABVD,
/ (/),
. , 2%
BEACOPPesc 3% / ( 5). ,
BEACOPPesc
60-65 ( ~17%!)60-62. <60
BEACOPPesc
~2%. , <1% <40
40-49 50-59 . ,
<60 ,
50-59 ,
40-49 60.
BEACOPPesc
ABVD 5.
, ,
BEACOPPesc
HL.
, ,
, ,
, ,
, COPP/ABVD
65-75 , 60-65
50-60 ,
Hodgkin:
221
5. (MDS/ANLL) BEACOPP-escalated ABVD HD9, HD12 HD15, 20012 ERTC 2 .
,
BEACOPP-esc x 8, HD960
BEACOPP-esc/base x (4+4), HD1261
BEACOPP-esc/base x (4+4), EORTC 2001264
BEACOPP-esc/base x (4+4), Italian65
BEACOPP-esc/base x (4+2), HD2000 GISL23
BEACOPP-14 x 8, HD1563
BEACOPP-base x 8, HD960
COPP/ABVD x 8, HD960
ABVD x 8, EORTC 2001264
ABVD x 6-8, Italian65
ABVD x 6, HD2000 GISL23
(#)
()
466
787
705
787
274
156
711
98
710
469
261
275
166
99
16-65
16-65
16-60
16-65
<60
17-60
16-60
16
16-60
16-65
16-65
<60
17-60
16
BEACOPP esc , BEACOPPesc

ABVD, , .
BEACOPPesc
HD12 GHSG61,
8 BEACOPPesc 4
BEACOPPesc 4 BEACOPP-baseline (4+4),
30 Gy
.
8 BEACOPPesc 4+4
FFTF 1.6%. ,
4+4 (3.3% 1.1%, p=0.006). ,
4+4

5-8,
, /.
, HD15 GHSG63
BEACOPPesc 8 6 BEACOPPbaseline 14 21 (BEACOPP-14).
60
60-65
()
(%)
107
78
48
78
46
61
48
41
48
111
122
46
61
41
1.7
2.4
2.1
3.4
1.8
3.2
0.8
2.0
0.8
1.5
1.9
2.2
0.6
0
MDS/ANLL
(%)
3.0
1.5
2.7
1.3
1.5
1.2
0.3
0
1.1
1.5
0.4
0.7
0.6
0
HD9 HD12. 6 BEACOPPesc FFTF

8 ,
BEACOPP-14 .

4 61, 6 0.8%,
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). / 3.0%
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BEACOPP
HD2000 GISL23, 6 ABVD
4 BEACOPP esc 2 BEACOPP
baseline, 6 COPPEBVCAD.
BEACOPP FFTF ABVD , ,
.
20012 EORTC 64.
, BEACOPP ABVD, ,
222
,
.
65, 4+4 6-8
ABVD (
) .
BEACOPP FFTF
, ,
( 5). ,

.
,

HL,
,
66.

Hodgkin;

ABVD BEACOPP,
PET-Scan .
ABVD
PET
PET ABVD

53,
>75%,
2 67. , , ,
68 , , (<75%).

( ) PET+
>2.5 HD15 GHSG, BEACOPPesc ( )63.
BEACOPPesc
PET
PET
BEACOPP HD12
GHSG61, 30 Gy
5 .
.. et al
1.5 . FFTF. 1.5

, 5- FFTF 6%.
,
, .
.
~23% , ,
.
BEACOPPesc
PET
PET-Scan. HD15 GHSG63
>2.5 . PET
BEACOPPesc BEACOPP-14 . 5-
92%
CR/CRu, PET-scan,
>2.5
. PET-scan, 86%
, >2.5 .
PET-Scan, .
PET-
>2.5 .
BEACOPPesc. PET

.
ABVD
PET
.
5- PET- ABVD ( ) 80%: ~88%
70-80% IV,
41. ABVD PET(+),
50%,
BEACOPPesc.
PET-Scan ABVD,
, .
, 80%
PET(-).
-
Hodgkin:
223
,
/ .
20% PET(+)
,
ABVD
.
,
PET(-) 53,
PET(+), .
,

HL >50%, 7,19,70,71.
,
IPS24.
, 72.

HL ,
.

,

,
.
6.

,
IL-10 73-75,
sCD3076-78, IL-1 IL-1RA78,
IL-678,79, TNF-80
TARC81. 2- 82,83.
519 , GELA 7 :
sIL-1RA, sIL-6 sCD3078. ,
, 3
5- FFTF <50%, 4% 14%
IPS 3.

- bcl-284,85,
-3 HRS86,87. , bcl-2
-3 .
88,89. CD20 HRS 90, -
,
Ann Arbor, -, ,
, ( )
( 1).
69,
13. ,
1 ,
ABVD .
3-6.
HL , (IPS),
1618 7. IPS 7 : 45 , ,
IV, Hb <10.5 g/dl, 15109/l,
<0.6109/l <8% <4 g/dl.
IPS,
5- FFTF 7-10% .
,
IPS
ABVD
70,71. ,
,
BEACOPPesc. , IPS -
.. et al
224
6.
.
/
HRS
sCD30, sCD8
CD15, CD20, -, MAL
sIL-10, sIL2-R, sIL-1RA

sIL-6, sIL-7, sIL-8,
TNF-, p55, p75, TARC
IL-6
sICAM-1, sVCAM-1
p53
Ki-67, PCNA, p27kip1, p53,MDM2, pRb,

p16INK4a,
bcl-2, -3
VEGF, MMP-9
MMP-2, MMP-9
: CD68, CD163
-: FOXP3+
-: TIA-1+
-:
Granzyme B+
-
, bcl-11A+
2-
CD1591,
-92 MAL93.
EBV , , 94-99.

.
CD68+ 100. ,
- (FOXP3+)
TIA1+ -
101.
bcl-11A
-
89. ( FFTF 75%
25%)89 PET HL.
.
,

. -
LMP-1, EBER1/2, aCTLs
,
RT-PCR 30 ( HRS ),
.
11 ,
IV 1/4
(5- FFTF <30%). IRF4
(HMMR, SENPF, CCNA2, CCNE2, CDC2),
(BCL2, BCL2L1, CASP3) (LYZ, STAT1)102.

, bcl11A

,
. ,

.
,
PET 2 ABVD (PET-2) , .
Hodgkin:
PET-Scan

PET-Scan

103-105.
, PET-Scan,

.

6 PET-Scan
2 106.

PET-Scan 2 ABVD (PET-2)
. , 5- FFTF 95% 10-15%
PET-2 103-105, PET-2
IPS105.
PET-2107. , , PET-2
, FFTF, PET-2,
IV105.

PET-2 IV107. ,
(Bologna Study)

PET-2.
(10-15%)
PET-2
. ,
, PET-2.
Deauville, PET-Scan 5-
,
108. 4 5, . ( SUVmax)
, PET-2. , International Validation Study
(IVS), 3- FFTF 95% 28%
PET-2 108,109.
PET-2
HL

PET-2 ,
-
225
ABVD.

2 Gallamini 110: 165 (53%
III/IV, 47% IIB 1 ) 2 ABVD PET2, Deauville.
83% PET-2 ABVDx4 . 17% (28
) PET-2 4
BEACOPPesc 4 BEACOPP-baseline (23
), 5 ABVD. 4-
PET-2- 92%. PET-2-
30% ABVD, 65%. , ,
BEACOPPesc
HL PET 2 ABVD.

PET 2 ABVD,
PET 2
BEACOPPesc . ,
, >50%
PET 2
BEACOPPesc111,112. ,
,
(4- FFTF 87%
PET-2), PET
2 BEACOPPesc
ABVD112.

PET2 , .
BEACOPPesc PET-2 ABVD,
GHSG, 2
BEACOPPesc, PET-2-
Rituximab
BEACOPPesc PET-2-.
, , Hodgkin
ABVD. -
.. et al
226

, ,

. , ,
(-
; ;), PET-Scan,

.
Hodgkin Lymphoma: First line treatment and prognostic factors

by Theodoros P. Vassilakopoulos, Georgios Boutsikas,
Andreas Sarris, Maria K. Angelopoulou
Department of Haematology, National and Kapodistrian University of Athens, Laikon General
Hospital, Goudi, Athens, Greece
Abstract: Hodgkin lymphoma (HL) is a highly curable malignancy of B-cell origin. Patients are
classified into early, intermediate and advanced stages based on the Ann Arbor staging system and the
presence of certain risk factors (mediastinal bulk, B-symptoms and ESR, number of involved nodal
sites and localized extranodal extension or age). Early stage patients (stages I/II without risk factors)
are treated with 2-4 cycles of ABVD plus 20-30 Gy involved field radiotherapy (IF-RT). Intermediate
stages (stages I/II with 1 risk factors) require 4-6 cycles of ABVD plus 30 Gy IF-RT, while more intensive chemotherapy improves tumor control without any overall survival benefit. In advanced stages (III/IV and probably IIB with mediastinal bulk and/or extranodal extension), BEACOPP-escalated is
superior to ABVD-equivalents in patients up to 60 years old, but potential benefits in terms of overall
survival are achieved at the expense of increased acute toxicity, toxic deaths and risk of secondary leukemias. Recent data suggest that limiting BEACOPP-escalated to 6 cycles instead of 8 may be associated with much lower rates of toxic deaths and leukemogenicity. Early response assessment with interim
PET may permit to limit treatment intensification with BEACOPP-escalated in a relatively small minority of advanced stage patients, who really need it. Post-chemotherapy PET-based evaluation of response
has already limited the need of RT in advanced stages; this is especially true after BEACOPP-escalated,
since the use of RT can be restricted to ~10% of patients. It is hoped that the optimal use of PET will also eliminate the need of RT in the majority of early stage patients in the near future. In addition to the
prognostic classification of limited stages reported above, the IPS remains the basis for the prediction
of outcome in advanced stages. Numerous novel biological prognostic factors have been described, but
have not been adopted in everyday practice because of issues of reproducibility and lack of prospective
validation. However, progress in understanding the biology of HL may lead to better risk classification
and provide a guide to individually tailored treatment in the forthcoming years.
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Principles of radiation therapy in Hodgkin lymphoma

by oannis Georgakopoulos1, vangelia Peponi2, iltiades richas1
Radiation Oncology Center, IASO Hospital, 2Radiation Oncology Department,
Ioannina University Hospital
Abstract: Radiation therapy plays an important role in the management of Hodgkin Lymphoma. In
combination with chemotherapy its role is irreplaceable as seen in many trials in relative literature. An
important issue in clinical practice is the additive toxicity of the two procedures. Regarding radiotherapy, total dose, extent of radiation field and treatment technique are the most important parameters that
affect the outcome. Large fields of radiotherapy (mantle, mini mantle, total or subtotal lymphoid irradi-
Hodkgin
237
ation) have been replaced initially by more localized treatment fields (IFRT - Involved Field Radiation
Therapy) and nowadays by more targeted therapies (INRT - Involved Node Radiation Therapy). Newer
sophisticated techniques of radiotherapy (IMRT Intensity Modulated Radiation Therapy, IGRT - Image Guided Radiation Therapy and PBRT Proton Beam Radiation Therapy) ensure more accurate delivery of radiation to target volume and reduce further more acute and late toxicity, which is of extreme
importance in Hodgkins lymphoma, as it concerns mainly young adults with curable disease and long
life expectancy.
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242
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.. et al
246
Treatment of relapsed/refractory Hodgkin lymphoma

by Maria K. Angelopoulou, Pagona Flevaris, Theodoros P. Vassilakopoulos
National and Kapodistrian University of Athens, Department of Hematology and Bone Marrow
Transplantation, Laikon General Hospital, Athens, Greece
Abstract: The majority of Hodgin lymphoma patients can be cured with modern chemotherapy combinations with or without radiotherapy. High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT/ASCT) is the treatment of choice for young patients (<65 years) who
are refractory to or relapse after initial treatment. With this strategy approximately 40-60% of refractory/relapsed Hodgkin lymphoma patients can be cured. Salvage chemotherapy given before HDT/ASCT
aims to disease control and peripheral blood stem cell mobilization and collection. For this purpose chemotherapy combinations containing cis-platinum, cytarabine, ifosfamide or gemcitabine are administered. The most important prognostic factors for the outcome of HDT/ASCT include the duration of first
remission, chemosensitivity to salvage chemotherapy, clinical stage and extranodal disease at relapse.
More than 80% of patients without any poor prognostic factors can be cured with HDT/ASCT. On the
contrary chemorefractory patients have significantly poorer prognosis, although 15-30% of them can
achieve long-term remission. New targeted therapies given either before or after ASCT as consolidation
might benefit poor risk patients and are currently under investigation. Disease evaluation by positron
emission tomography before ASCT offers new prognostic information and is being evaluated in clinical trials. Older or ineligible patients with primary refractory/relapsed Hodgkin lymphoma are usually
treated with conventional salvage chemotherapy with a <30% chance of long-term disease control. Selected patients with localized relapse can be treated with salvage radiotherapy.
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of involved field radiotherapy to high-dose chemotherapy

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A

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2
, , Adjunct Assistant
Professor of Hematopathology The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
: , ,
75, , 11527, .: 210-746-2195, Fax: 210-7462179
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257
Biologic Basis of Novel Therapeutic Strategies in Hodgkin Lymphoma

by Elias Drakos1, George Rassidakis2
Lecturer of Pathology, Medical School, University of Crete, Greece, 2Assistant Professor of
Pathology, School of Medicine, National and Kapodistrian University of Athens, Greece, Adjunct
Assistant Professor of Hematopathology The University of Texas M.D. Anderson Cancer Center,
Houston, TX, USA
1
Abstract: The development of traditional treatment for Hodgkin lymphoma patients remains one of
the most successful efforts in cancer therapeutics. Surprisingly, this success was largely accomplished
independently of the understanding of the disease biology. However, even today a proportion of patients
succumb to the disease and the long term treatment side effects remain considerably debilitating. Nowadays, accumulating biological knowledge gained from recent studies that explored the mechanisms of
Hodgkin lymphoma pathogenesis provides a solid basis and rationale for the development of novel experimental, and biologically more targeted, therapeutic approaches. Among others, understanding of the
significance of activation of NF-kB transcription factor and the PI3K-AKT-mTOR signaling pathway,
as well as the potential role the CD30 receptor for the survival and proliferation of Hodgkin and ReedSternberg neoplastic cells has revealed new therapeutic molecular targets for the disease. In addition,
modulation of the p53 tumor suppressor pathway using non-toxic small molecules may provide a promising targeted therapeutic strategy in near future. Based on the biology of disease, selection of patients
in newly designed clinical trials should take into account both genetic (i.e. gene mutations) and signaling pathway markers to better define subgroups for personalized therapeutic interventions. Application
of novel therapeutic agents based on specific molecular targets has already been translated in a multitude of clinical trials providing encouraging results in an effort to increase the curative potential and decrease the therapeutic side effects patients with Hodgkin lymphoma.
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A
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. ,
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, , .
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IV HDACs. , mocetinostat
85mg per os
7/28 (25%) (PR) 16. ,
CR,
2
(110mg) mocetinostat , , .
ITF 2357,
HDAC, HDACi
. et al
262
Hodgkin.
13 17 , , ,
ITF 2357 19 , 18. CR PR
12 18% ,
. , 2008,

.

19
5q-20. , 2/15
PR, , (25mg/
21 28 )21. ,
22, ORR
19% (1 CR 6 PR), 6/36 .
ORR (1 CR 11 PR) 50%
24 23.
,
Hodgkin, .
Everolimus
mTOR (mammalian target
of rapamycin) ,

24,25. Hodgkin ,
temsirolimus, Hodgkin everolimus,
. everolimus
10mg 28 19 ( 84% ASCT)26. ORR 47% (1
CR, 8PR), 8/19 .
7.2 ,

25.2 .

3/4 32% 4 ,

temsirolimus25. , ORR,
,
Hodgkin everolimus,

( 37 ) (ECOG<2)
Hodgkin.
Rituximab
-CD20
Hodgkin 27, CD20
Reed-Sternberg 22% Hodgkin28,
.
6 rituximab (375 mg/m2) 22
Hodgkin ORR
22% (1 CR) 7.8 ,
6 29.
CD20 Reed-Sternberg,
rituximab .

rituximab

rituximab. Younes .30 Kasamon .,31
,
. ,
rituximab 78
( , IV) 375 mg/
m2 ABVD 6 30, 26 . EFS 5 83% OS
96%, >2 (IPS)32 EFS 73%.
3/4 23% ,
. Kasamon .31 69%
Hodgkin
48 -IV,
rituximab 375 mg/m2 1,
8, 15 22 ABVD 2,4 6. 3 EFS OS 83%
98% ,
, 16/49 26 ,
.
,
. CD20+ Reed-Sternberg 20%30
8%31,
. , Kasamon
.31
,
Hodgkin33,34 .

Hodgkin ,
, .

Hodgkin
, 2040% ReedSternberg EBV35. ,
EBV
36 Hodgkin.
Bollard 37 LMP2- . 3
Hodgkin 2
CR (13 32 ), 5/5
263
(
6-24 )37.

Hodgkin,
,
,
38. ,
-CD19
(CAR19) 39-41.
Hodgkin
/ .

,
, . EFS ,
BEACOPP
ABVD.

PET/CT. ,
/
,
.
. et al
264
/ Hodgkin . .
Brentuximab vedotin6
Vorinostat13
Panobinostat15
Lenalidomide21
Lenalidomide22
Lenalidomide23
Everolimus24
II
II
II
II
II
II
II

102
25
129
15
35
24
19
PR
41%
4%
23%
13%
14%
46%
42%
CR
35%
0%
4%
0%
3%
4%
5%
ORR
75%
4%
27%
13%
17%
50%
47%
CR= , PR= , ORR=
Targeted therapy in Hodgkin lymphoma - Clinical aspects

by oannis tsianidis, mmanouil Spanoudakis, onstantinos satalas
Department of Hematology, Democritus University of Thrace Medical School,
Alexandroupolis, Greece
Abstract: Hodgkins lymphoma is one of the first cancers to be rendered curable by combination
chemotherapy. Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) is considered as the standard
of care for most patients as it offers an excellent balance of efficacy and toxicity. However, though the
majority of patients can be cured with ABVD or alternative regimens even in advanced stages, recurrent and refractory disease remains a significant problem. Additionally, long-term toxicity is becoming a
major issue, as survivors cured of Hodgkins lymphoma outnumber the patients with active disease. Advances in our understanding of the pathobiology of the disease culminated in the development of novel
targeted therapies, many of which have demonstrated remarkable activity in the relapsed/refractory setting and are currently investigated as frontline treatment.
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N, Engert A. First line treatment of advanced stage Hodgkin
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evidence of disease response to the pan deacetylase inhibitor
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patients with relapsed/refractory Hodgkins lymphoma after
autologous stem-cell transplantation: results of a phase II
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classical Hodgkins lymphoma: an open-label, single-arm,
phase 2 trial. Lancet Oncol. 2011;12:1222-1228.
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18. Carlo-Stella C, Guidetti A, Viviani S, Gianni AM. Phase
II trial of combination of the histone deacetylase inhibitor
ITF2357 and meclorethamine demonstrates clinical activity and safety in heavily pretreated patients with relapsed/
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the use of lenalidomide in relapsed or refractory multiple
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A
Hodgkin
1, 2, 1
: (alloHCT) Hodgkin
(RICHCT). ,
, , . Hodgkin
, Reed-Stenberg
HCT, ,
.
Hodgkin,
, . ,
, . (60%) NRM (21%) 3 .
RICHCT autoHCT . HCT,
. . RIC-HCT ) , , )
, , ) DLIs, ) PET
DLIs, ) brentuximab vedotin ) CTLs - .
RIC-HCT . RIC-CT, . , ,

RIC-CT .
Hodgkin (Hodgkin lymphoma, HL) , .. ,

2
- , , ,
: , , ,
... , e-mail: panagtsirigotis@gmail.com
1

, ,
80-85% 65-80%
ABVD .1,2

1 ,
-
Hodgkin

(autoHCT).3,4
,
70-80%. 20%

autoCT .5

, , autoHCT
. , (alloHCT) ,

,
-
[graft vs. Hodgkins Lymphoma effect, Gv(HL)].
Gv(HL)
HL Gv(HL) (graft vs. host disease, GvHD)

,
.6,7
(European group for Blood and Marrow Transplantation,
) (GITMO)
GvHD
.8,9
(
, , ..) .

(donor lymphocyte infusions, DLIs)
GVL Gv(HL)
HL. DLIs
alloHCT, ,

per se.
Peggs ., 5
alloHCT anti-CD52
(Campath-1H), DLIs , (
675 ).10
267
18 DLIs
, 44% , MDACC
33% .11,12
HL
,

.

alloCT autoCT, -
(non relapse mortality,
NRM).6,13 ,
,
( 60%) alloHCT
autoHCT
.14 NRM ,
Gv(HL) .

(reduced intensity conditioning, RIC)
Gv(HL)

- .
autoCT RIC-alloCT Thomson
5- (DFS)
34%, , (1/34 ).15
GITMO autoCT RIC-alloCT
. (S) DFS (66% vs. 42% 39% vs. 14%).9

Hodgkin

HL
HCT
2000. EBMT
2000 50 alloHCT HL
2009 300 -
268
250 RIC-HCT. 2000,

5% HL auto-HCT alloHCT.
.7,13,14
1982 1998 EBMT 1185
.16 , alloHCT
(81.5%) 231
NHL, 147 NHL, 255 NHL, 314
, 71 Burkitt,
167 HL. 14687
autoHCT. : 1) 4- S
HL (27%),
51% NHL, 38%
NHL, 41% NHL, 42% , 37%
Burkitt. 2) S
HL NRM (52%). 3)
OS
autoHCT, , 4)
alloHCT.
alloHCT HL.

NRM

autoHCT.8,17

1990 alloHCT (RIC-alloHCT) .
RIC
NRM, alloHCT
-
alloHCT.
alloHCT HL.

RIC-alloHCT HCT 1
. et al
. 3- NRM 23% RIC-HCT

, 46%, (p=.001). OS
PFS , 22% vs. 28% 20%
vs. 18% RIC-HCT HCT . 8

alloHCT R.

autoHCT.

alloHCT HL 1.
1 : 1) alloHCT RIC
autoHCT. 15% - 20%.
2) -

. 3) .
alloHCT
50%
35% - 40%.
alloHCT
autoHCT. 4) alloHCT
,
. 5) DLIs
30%, , 6)
:
alloHCT, alloHCT, GVHD, 7)
,
GVHD.
,
alloCT. (25-30%),
alloCT
L. /
autoHCT
6 11
6 14
8 15
6 11
9 16
, O

, O

,

,

, O

21 64
, O

, O

, O

4 7
, O

3 8

14 25
, O

FM: fludara-melphalan, FC: fludara-cyclophosphamide, T: Thiotepa, TBI: total body irradiation, FB: fludara-busulfan, B: BiCNu, ATG: antithymocyte globulin
()
No -
/
()
()
()

Robinson18
52
36/16
FM, FC, FCT,
17.3% 2
42% 2 56.3% 2
(2002)
FBM
40
20/ 20
31/9
FC-ATG
22% 18
32%
61% 18
Anderlini26
(2005)
FM
18
67
67/0
53/14
FM vs.
29% vs.
25% vs.
39% vs.
Peggs27
(2007)
FM-Campath
7% (1-)
39% (4-) 62% (4-)
24
14/10
24/0
FC FM-Campath
8% 1
47% 2
71% 2
Castagna19
(2009)
23
3/20
20/3
FM, FC, FB,
22% 1
27% 3
59% 3
Johansson20
(2011)
FC-TBI
285
180/105
229/56
FM, FC, FCT,
19.5% 1
25% 3
29% 3
Robinson11
(2009)
TBI-Flu
122
67/55
122/0
FM, FC, FB,
14% 1
39% 2
66% 2
Sarina9
(2010)
FCT, FC-TBI
14/0

55% 4
Kaloyannidis25 14
(2012)

Peggs10
49
31/18
44/5
FM-Campath
16.3%
32.4%
55.7% 4
(2005)
2
4
40
38/2
29/11
FM
25% 1
32% 2
48% 2
Alvarez22
(2006)
38
25/ 13
38/0
FM-Campath
19% 5
34% 5
65% 5
Thomson15
(2008)
58
25/33
48/10
FM FM-ATG
15% 2
32% 2
64% 2
Anderlini12
(2008)
78
55/23
67/11
FM
19% 4
24% 4
43% 4
Sureda23
(2012)
1.
Hodgkin
269
270
.
alloHCT :
Thomson ., 5- OS
PFS 51% 34% RIC-CT,
-, 2 ,
.15
Castagna .
(n=44), OS 71%
RIC-HCT 50%
(p=0.03). NRM 8%
0%
.19 RIC-HCT (n=122)
autoHCT
(n=63). H 2- OS PFS 66% vs. 42% 39%
vs. 14% (p <,001).9
Memorial Sloan Kettering Cancer
Center (MSCCC) autoHCT. RICHCT 40 ,
-
19 .24

autoCT.
RIC-HCT
4- S 40%,
.
RIC-HCT autoCT,
40
- 28 .25
autoHCT alloHCT (tandem

auto-allo HCT) HL.

autoHCT
( 3-6 )
alloHCT ( )
GVL
. Tandem auto-allo HCT HL,
.
-
. et al
, , /
autoHCT.28

,

.29,30
.
-. GVHD .
HL.
HL,
PFS 25%
. PFS 0%.

Epstein Barr (EBV)
Reed-Sternberg
- (Cytotoxic Tlymphocytes, CTLs)
.
EBV , latent membrane protein-1 &-2
(LMP1, LMP2)

CTLs.31,32

Baylor College of Medicine (BCM) 14
CTLs LMP .
, ( 6 ),
5 40 .33
EBV .
CTLs 8
(5 2 3 )
HL.
7 18-32 .34
60-70% HL LMP1&2
Hodgkin

. Cruz .
CTLs
MAGE-4,
- EBV- HL.35

-
. Geterman .
CTLs Survinin, MAGE4, SSX2, PRAME, NY-ESO1
Hodgkin.36
EBV
Reed-Sternberg

-
.
- (chimeric antigen receptor,
CAR) CD30 Reed-Stenrberg,
.
.37,38
BCM
- EBV CAR
CD30. -

CAR .39
HL ,
HL-
.40,41
HL,
.
-
-
271

alloHCT HL.
A.
HL, :
1)
-
2)
alloHCT.
alloCT
.
alloHCT, .

alloHCT
.
3) -
.
.
B. alloHCT,
RIC
Gv(HL) RM.
. DLI /
. GvHD
DLI.
. RIC-HCT. brentuximab
vedotin 18 , GVHD
. ,
RIC-HCT 25 brentuximab
vedotin 50% () 38% , .
, .
E. autoHCT 1
HL. alloHCT
, .
. et al
272
Allogeneic hematopoietic stem cell (allo-HSCT) transplantation

in Hodgkin lymphoma
by Panayotis Kaloyannidis1, Panagiotis Tsirigotis2, Ioanna Sakellari1
Department of Haematology and Bone Marrow Transplantation, Papanikolaou General Hospital,
Thessaloniki, 2Second Department of Internal Medicine, Propaedeutic, University of Athens,
University General Hospital Attikon, Greece
Abstract: The role of allogeneic transplantation (allo-HCT) in Hodgkins lymphoma (HL) remains
controversial and needs to be further investigated in the era of reduced intensity conditioning regimens
(RIC). AlloHCT with the use of myeloablative conditioning was associated with significant non-relapse
mortality (NRM). However we should take into account that the vast majority of patients were heavily pre-treated with significant co-morbidities. The indirect evidence of graft versus Hodgkins lymphoma effect was defined by studies which report that the administration of donor lymphocyte infusions
(DLIs) is beneficial, even without preceded chemotherapy.he rationale of allo-HCT in HL is based on:
a) graft versus Hodgkins effect, b) the absence of Reed Stenberg in the graft, c) correction of disease
related immune-suppression, d) inadequate graft collection for autologous HCT, and e) prevention/correction of therapy-related genetic abnormalities. Along with developments in transplant procedure after
2000, ie the introduction of alloHCT with reduced intensity conditioning (RIC-HCT) which resulted in
a significant lower NRM, the role of alloHCT in patients with HL needs to be re-considered. In a EBMT
retrospective study, the probabilities of 3-year OS, PFS, and NRM in 285 patients who received various
fludarabine-based RIC regimens were 39%, 25%, and 21% respectively. High relapse rate (up to 60%)
emerged as the major cause of failure. Similar results were reported in a large prospective phase II cooperative study conducted by EBMT and Spanish group. Four-year PFS was 24% for the whole cohort,
while patients transplanted in CR had a better outcome. Predictive negative factors which influence the
outcome were: poor performance status, chemo-refractory disease, and a short PFS after autoHCT. The
recently published Greek experience, examined the outcome of patients with relapsed disease post autoHCT. Nineteen patients underwent RIC-HCT and the probability of 4-year OS was 55%. Moreover, a
prognostic system was proposed based on the presence of 3 factors with a negative impact on OS: a) relapse within a year post autoHCT, b) chemorefractory disease at the time of auto HCT, and c) B-symptoms at relapse. Further improvement of the efficacy of alloHCT is needed and future studies should
focus on several issues: a) definition of criteria for patient selection, ie patients with low-tumor burden
and chemosensitive disease, b) intensification of conditioning regimen without increasing toxicity, c)
prophylactic or preemptive DLIs, d) PET-CT scan for early diagnosis of disease progression and treatment with pre-emptive DLIs e) targeted therapy with brentuximab vedotin, and f) emerging cellular therapies using CTLs with specificity against antigens expressed on the surface of Reed-Sternberg cells. The
planned tandem autoHCT followed by RIC-HCT needs further testing, while the optimal RIC conditioning-regimen has not been established so far. Based on current evidence, only patients with chemosensitive relapse after autoHCT should be considered as candidates for alloHCT.
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The role of 18FDG PET/CT in the evaluation of Hodgkin lymphoma

by Phivi Rondogianni1 and Ioannis Apostolidis2
Department of Nuclear Medicine-PET/CT, 2Department of Haematology and Lymphomas
and Bone Marrow Transplantation, Evangelismos General Hospital, Athens, Greece
Abstract: 18FDG PET/CT is a noninvasive imaging modality widely used in patients with diverse
malignancies, especially those with lymphoma. PET/CT has been evaluated in primary staging, restaging after the end of therapy, early estimation of the therapeutic result as well as in post therapy surveillance. The method has been demonstrated to be more sensitive and specific than either 67Ga scintigraphy
or computerized tomography in the distinction between scar or fibrosis and active tumor. Data to support these different roles still need validation by even more prospective studies. Moreover caution must
be exercised in the interpretation of PET images to avoid false positive and false negative results. Recent attempts to standardize PET interpretation criteria as well as to incorporate it in uniformly adopted response criteria are hopeful for the improvement of lymphoma patients outcome. Results of the
use of PET during and after completion of therapy for staging of Hodgkins lymphoma demonstrate a
highly predictive value for outcome but there are problems with the interpretation of results. PET response-adapted therapy is experimental and is the subject of ongoing appropriately designed clinical
trials. Clearly, well designed clinical trials are warranted to determine the subsets of patients that will
benefit from this modality.
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Hodgkin.
Long-term complications of treatment for Hodgkin lymphoma

by Paraskevi Roussou1, Stamatis Karakatsanis2
Associate Professor of Internal Medicine-Hematology, Hematology Unit, 3rd University Department
of Internal Medicine, General Hospital of Chest Diseases Sotiria, 2Hematology resident,
Hematology and Lymphomas Clinic and Bone Marrow Transplantation Unit, General Hospital of
Athens Evaggelismos
Abstract: Hodgkin lymphoma is a relatively rare malignancy in the general population but shows an
increased incidence in young people. Although combination therapy has evolved, leading to extremely
high cure rates and allowing reduced doses of both chemotherapy and radiotherapy, minimizing late effects of treatment has traditionally been a challenge. These include cardiovascular, respiratory, endocrine,
developmental and psychological complications and the occurrence of secondary malignancies. These
complications are important causes of increased mortality among survivors of Hodgkin lymphoma. Periodic monitoring for some of those complications is recommended in the hope that early diagnosis can
lead to better treatment. Therefore, patients with Hodgkin lymphoma in complete remission should be
Hodgkin
293
periodically evaluated and monitored not only for recurrent disease but for possible long-term complications as well. It is worth noting that the combination therapies administered today are designed to be
less toxic than the original ones, in an effort to reduce the incidence of complications. However longterm monitoring is still needed to fully assess their own complications, while it seems that interim PET/
CT in combination with more accurate prognostic markers and more effective drugs will be exploited in
pursuit of the optimal therapy in Hodgkins lymphoma.
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A
Hodgkin

. ,
: Hodgkin (Nodular
Lymphocyte-Predominant Hodgkins Lymphoma, NLPHL) , 5%
Hodgkin . NLPHL
Hodgkin (cHL) ,
. cHL ReedSternberg (RS), NLPHL
(lymphocytic and histiocytic, LP cell). LP , RS , CD20 CD45,
CD15 CD30. cHL, NLPHL ,
[ Ann Arbor (AAS) I/II] 80%
.
. , rituximab
+ .
Hodgkin (NLPHL)
HL, 5%
HL, . NLPHL
Hodgkin (cHL) .
NLPHL
Reed-Sternberg (RS) cHL, /
(Lymphocytic and histiocytic cell, L+H cell,

(WHO) 2008, Lympocyte predominance cell, LP cell).
LP -
, ,
: . , , , ,
, email: florankontopidou@
hotmail.com
(CD20, CD19, CD22, CD79a) CD45

CD15 CD30, cHL.
,
. WHO,
NLPHL .
,
cHL.
.

. 10-
>90%, IV.
,
.
Hodgkin
NLPHL
B-NHL
HL. Revised European American Lymphoma 1994
(REAL classification) NLPHD cHL
HL, WHO 2001 2008.
299
(L+H LP)
5% HL NLPHL. NLPHL
8-9
10.000.000 . ,
.
NLPHL 35-40 .
2
>40 . 3:1 .1,2
NLPHL
Reed-Sternberg (RS)
(L+H) , popcorn LP (WHO
2008, ).
LP RS cHL. RS
CD15+, CD30+, CD45-, CD20. LP CD30-, CD15-,
CD45+, CD20+, CD19+, CD22+, CD79a+, BCL6+4. To
CD30 4. RS Oct-2 B-1,
LP ( 1).
LP
. ,
cHL .5
NLPHL . . NLPHL
-
(germinal centre, GC)
-
. LP
BCL6, GCET1 LMO2,
, Oct-2 BOB-1.
(Single cell polymerase chain reaction assays, PCR) LP
(Ig)
Ig mRNA.
Ig,

. ,
LP ,
CD3, CD4, CD57, BCL6, PD1.
Epstein-Barr (EBV)
cHL, NLPHL.3
-

NLPHL. (reactive follicular hyperplasia)
(progressive transformation of germinal centers). .
NLPHL

, CD21+
(FDCs)
, LP.
cHL, , .
NLPHL CD20+, CD79a+
. LP CD4+ T ,
CD57+ , , 6 ( 1).

30 >1500 NLPHL.

,
cHL
(LRCHL) .
4 NLPHL, :1,2,7,8
(100%). 50-60% NLPHL,
>6-12 .
.. .
300
1. odgkin (cHL), Hodgkin

(NLPHL) - -/
(T/HRBCL)
cHL
RS
NLPHL
LP : L&H popcorn
T > B
B > T ,
, , CD4+CD57+ T-
,
, CD21+ FDC
, ,
,

CD45
CD20
CD79a
CD15
CD30
OCT-2
BOB-1
PU-1
EMA
BCL-2
BLC-6
-/+
+
+
-/+
-/+
+
-/+
+
+
+/- (80%)
+
+
+
+/+
T/HRBCL
LP
, ,
R-S
>B , CD8+

+
+
+/- (40%)
+/+
+
-*
+/+*
+/-
cHL: classical Hodgkin lymphoma; NLPHL: nodular lymphocyte-predominant Hodgkin lymphoma; T/HRBCL: T-cell/histiocyte-rich B-cell lymphoma; FDC: follicular dendritic cells; EMA: epithelial membrane antigen; *: .
.
2-7%

15-30% .
NLPHL, ,
.9
, cHL.
,
,
10% .
2-3% <3%.

.
B (6-
15%), (T)
(LDH).
NLPHL ( 80%)
( ,
) 50-60%
cHL.
,
, NLPHL. European Task Force on Lymphomas (ETFL),
426 HL
Rye.
-
Hodgkin
REAL, NLPHL
51% , cHL
(LRCHL - 27%), cHL (5%), NHL (3%)
(3%).10

,
.
LP ,
,
( 1).
NLPHL ,
, ( ) .
. ,
,
-
- [T-cell/Histiocyte-Rich Large B-cell Lymphoma (T/HRLBCL)].

NLPHL ,
NLPHL
. NLPHL :

(Progressive transformation of germinal centers, PTGC). , ,
, . 5-10%
- (
), 20% .
PTGC
NLPHL LP . 10%-30%
PTGC HL, NLPHL ,
11-13
. PTGC
NLPHL, PTGC .
.
Hodgkin (Lymphocyte-Rich Classical Hodgkin Lymphoma, LRCHL).
cHL, LRCHL NLPHL NLPHL
301
cHL. , 1/3
NLPHL LRCHL.

,
. LRCHL
R-S, LP.
(CD30+ CD15+ LRCHL).
CD20
CD30. 40% LRCHLs EBV+.
-
- [T-cell/Histiocyte-Rich
Large B-cell Lymphoma (T/HRLBCL)]. NHL -
.
- (DLBCL, <5% ).

NLPHL, .
NLPHL
. NLPHL T/
HRLBCL,
2 .
T/HRLBCL NLPHL.
NLPHL, T/HRLBCL CD20+ B-
.
T/HRLBCL LP ,
, R-S.
. NLPHL
-, CD3+CD4+CD57+
T-,
, T/HRLBCL CD8+ - - . NLPHL
, T/HRBCL
.14,15 ( 1).

NLPHL
cHL.
-
.. .
302

90-100%. (>13 )
44%, DLBCL, 5-21%.16-20
3-6 ,
,

NLPHL. () 10- >90%, ETFL
IV (<50%).10
GHSG (German Hodgkins Study Group) 394 NLPHL 7904 cHL
9 , . , ABVD, COPP/
ABVD BEACOPP /.11,21,22 cHL, NLPHL
, (Freedom From
Treatment Failure FFTF) 50 . NLPHL
cHL NLPHL
.
, FFTF
NLPHL cHL. LPHL
FFTF , (Hb<10.5 g/dl) , 45 ,
(Hb<10.5 g/dl).1
DLBCL, NLPHL .23
DLBCL NLPHL
Miettinen .24 10%
NLPHL, DLBCL 4-11 NLPHL. 14%.
,
.
28% .25

. ,
202 NLPHL , 5/41
11/41 , 8 -
.26 ETFL, 31 ,
8 , 4 10
(2 NHLs, 5
3 ). ,

,
.27
NLPHL . ,
NLPHL
cHL,
90%, cHL.21

. 6% NLPHL

.28,29

, (), ().
IA IIA
cHL ,
NLPHL. .

.
IA
IIA - 3036 Gy. 30Gy
, .
:
, ,
.
. European Network Group
58 (54 IA) , 50
() 57%.30,31
Hodgkin
,
(
+),
(90100% vs 42-69%),
.30,32,33 , ,
.
: ,
, .34 30-36Gy
/. 113 93
13 +, 25 , 35 46 . 10
FFTF 89% 72%
96% 100% .
FFTF .21
: ,
HL, (ABVD, EBVM) ,
, .34,35

20Gy.34
2 3 2
3 .34,36,37

VAMP 28 .38
M.D. Anderson Cancer Center, (37 ) (11 ), 9.3
,
.
NLPHL,
100% 6 ,
+ .
.
:
,
303

, PET-scan
.39,40 ,
(CVP) ,

+.40,41
, .42
.
Rituximab: rituximab, ,
, .

25% 43 .
CHOP
B-NHL, ABVD
.43,44
+rituximab NLPHL
.28,43
IB IIB

, I/II ,

IA/II.26

20-25% NLPHL III IV.
cHL .
ETFL10 219
NLPHL, III
IV 14% 6% . , +.
8 , FFTF
III 94% 62% IV 41%
24% . GHSG,
.. .
304
8- FFTF
75% COPP/ABVD BEACOPP
.1
, ABVD

.20

,
PET- .
anti-CD20,
rituximab, ,
NLPHL
1999. (
) rituximab (375mg/
m2, 4 )
. .
6 , 94%
33 .45,46,47
,
, ofatumumab .
rituximab ,

cHL. ,

.48,49

NCCN, ,
, 30-36 Gy, -
(Grade 1C) 2-3 ABVD 20 Gy.

(Grade 2C). ,
+ .
rituximab .
.
(, IV) cHL. 8
ABVD .
( CVP)
ABVD,

. rituximab
.

,
.
NLPHL ,
cHL, LRCHL,
.50 NLPHL LP RS .
NLPHL
PTGC, LRCHL T/HRBCL,

.

.

, cHL. NLPHL IA/IIA
, +.

NLPHL : ) ,
, ) o
, ) rituximab
, )
HL .
Hodgkin
305
Nodular lymphocyte predominant Hodgkin lymphoma

by Flora N. ntopidou, Theoni anellopoulou
Second Department of Internal Medicinec, National and Kapodistrian University of Athens,
Ippokration General Hospital, Athens, Greece
Abstract: Nodular Lymphocyte-Predominant Hodgkins Lymphoma (NLPHL) is rare, accounting for
approximately 5% of all Hodgkins lymphoma (HL) cases in Western countries. NLPHL and classical
Hodgkin lymphoma (cHL) differ substantially in their histopathology, presenting features and clinical
course. The neoplastic cell is the lymphocytic and histiocytic cell (LP cell), rather than the ReedSternberg (RS) cell of cHL. Unlike the RS cells, LP cells express both CD20 and CD45 (leukocyte common
antigen) and are negative for CD15 and CD30. In comparison with cHL, NLPHL presents with a striking male predominance, while the disease is localized [Ann Arbor stages (AAS) I/II] in more than 80%
of the patients and is rarely associated with B-symptoms and mediastinal involvement. Since this disease is so uncommon, most information concerning treatment and outcome has come from reports of
single institutions or pooled, multi-institutional retrospective analyses. As a result, treatment recommendations in NLPHL are diverse and range from noncurative options, such as watchful waiting or singleagent rituximab, through involved field radiation alone or combined modality therapy.
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(PTH-Rp).80
Unusual clinical manifestations and complications of Hodgkin lymphoma

by Argiris S. Symeonidis
Hematology Division, Dept of Int.Medicine, University Hospital of Patras, Greece
Abstract: In addition to the classical or conventional clinical manifestations of Hodgkin lymphoma, altogether consisting a frequency of about 80-85% of all the cases, in this type of lymphoma many
rare and atypical clinical manifestations, as well as some rarer paraneoplastic syndromes, have been described. Among the former, primary extranodal disease, which is rarer, than that developing in Non Hodgkins Lymphomas, can originate in any tissue or organ of the body. Among the atypical or uncommon
clinical manifestations, alcohol-induced nodal or bone pain is a well-recognized, but rarer impressive
manifestation. Various hematological findings may be encountered, including anemia of different severity, leukocytosis with neutrophilia, thrombocytosis, eoasinophilia, and pancytopenia sometimes with in-
..
318
creased marrow fibrosis. Autoimmune manifestations, either organ-specific or not, are not uncommon,
and may be clustered in some patients. The paraneoplastic syndromes are organ- or system-specific manifestations, which cannot be interpreted by the infiltration or the participation of the affected organ, but
result from a long-acting hormonal, humoral, immunologic or other as yet non-clarified pathogenetic
mechanism. Among these diseases, neurological syndromes, such as subacute cerebellar degeneration,
progressive multifocal leucoencephalopathy, stiff-person syndrome, various peripheral, axonal poly-radiculoneuronopathies, and other rarer syndromes are included. Among the remaining paraneoplastic syndromes, the vanishing bile-duct syndrome, idiopathic cholestasis, minimal change nephrotic syndrome,
various bullous skin disorders, granulomatous vasculitis of the CNS and the orbit, uveitis-chorioretinitis, amyloidosis, clubbing, hypercalcemia, myasthenia gravis, ichthyasis, polymyalgia rheumatica, and
hyperprolactinemic galactorrhea are included. Awareness about these atypical and uncommon cli nical
manifestations and their prompt recognition is particularly important for any clinical hematologist, and
might be crucial and life-saving for the patient, since the majority of these syndromes and manifestations are at least stabilized and may be completely reversed, following the administration of the appropriate anti-lymphoma treatment.
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Hodgkin lymphoma in specific subgroups of patients

by Katerina Pyrovolaki, Maria Psillaki, Helen A. Papadakis
Hematology Clinic, University Hospital of Heraklion, University School of Medicine Crete, Creece
Abstract Hodgkin lymphoma sometimes presents coincident with certain other major conditions,
including pregnancy, infection with human immunodeficiency virus (HIV) or older age, which complicate treatment and make management considerably more challenging. Between 0.5% and 1.0% of cases
of Hodgkin lymphoma present coincident with pregnancy. Treatment should mimic that of nonpregnant
patients as much as possible, taking into consideration the gestational age at presentation, the clinical
stage of disease, and the preference of the patient. Whenever possible, treatment should be deferred at
least until the second trimester, after the completion of organogenesis, as chemotherapy in the first trimester can induce a spontaneous abortion or significantly increase the risk of congenital abnormalities.
Some patients may be candidates for deferred therapy after the first trimester. However, disease that seriously threatens the immediate well-being of the mother (eg, acute airway obstruction, spinal cord compression) requires emergent treatment at any time. In general, the majority of pregnant women diagnosed
with Hodgkin lymphoma have good pregnancy outcomes and their prognosis does not differ significantly from nonpregnant women. The availability of highly active antiretroviral therapy (HAART) has led
to improvements in immune status among HIV-infected persons, reducing AIDS-related morbidity and
prolonging survival. However, despite the impact of HAART on HIV-related mortality, malignancies
remain an important cause of death in the current era. Hodgkin lymphoma in the HIV-positive population is characterized by frequent B symptoms (ie, fever, weight loss, night sweats), extranodal disease,
and involvement of unusual locations. The most common sites of extranodal involvement are the gastrointestinal (GI) tract, bone marrow, liver, lung, and central nervous system. The treatment of systemic
Hodgkin lymphoma in the setting of HIV is complicated by the patients immunocompromised state and
. et al
326
also requires specific treatment for the HIV. Supportive care should also include prophylaxis for Pneumocystis jiroveci pneumonia and antibiotic prophylaxis for enteric organisms. Given the high incidence
of recurrent Herpes simplex, Herpes zoster, and Candida infections in this population, many clinicians
also advise instituting antiviral and antifungal prophylaxis. Older Hodgkin lymphoma patients defined
by chronological age represent a heterogeneous population in terms of life expectancy, comorbidities,
and functional status. Older patients have lower remission rates, but relapse-free survival is less impaired. No standard treatment recommendations exist. In older fit patients less than 6570 years go for
young treatment. The thoroughly estimation of the individual patients frailness/comorbidities is mandatory in order to properly adjust treatment, thus saving patients from over/under treatment. Representativeness of large clinical trials including evaluation of functional status and comorbidity remains crucial.
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cis-
DHAP: , , cis-
ICE: , ,
DICE: , , ,
IGEV: , , ,
GND: , ,
GN: ,
GDP: , , cis-
BEAM: , , , -
(Dexa = )
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3 - 3

: , 27, 115 23 , .: 210 7211806

Haema 2012; 3(3): ii-vi

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind,

Haema 2012; 3(3): vii

Hodgkin lymphoma: histological features and classification ..................................................................................... 185

Biology of Hodgkin Lymphoma ............................................................................................................................................. 190

Principles of radiation therapy in Hodgkin lymphoma ................................................................................................. 231

Treatment of relapsed/refractory Hodgkin lymphoma ................................................................................................ 239

Biologic basis of novel therapeutic strategies in Hodgkin lymphoma .................................................................... 250

Targeted therapy in Hodgkins lymphoma Clinical aspects ..................................................................................... 260

Long-term complications of treatment for Hodgkin lymphoma .............................................................................. 285

Nodular lymphocyte predominant Hodgkin lymphoma ............................................................................................. 298

Unusual clinical manifestations and complications of Hodgkin lymphoma ........................................................ 307

Hodgkin lymphoma in specific subgroups of patients ................................................................................................. 321

. Pyrovolaki, M. Psillaki, H.E. Papadakis

: - (Nuclear factor-) HRS.

HL, (5%) HL (95% ), /

Hodgkin lymphoma: histological features and classification

1. WHO Classification of Tumours of the Haemopoietic and

Hodgkins disease. Am J Pathol. 2001; 159:1807-1814.

Hodgkin (HL), (WHO)

pop-corn (LP cells).

2. - (Nuclear factor-B) HRS.

CD40, CD30, TNF, RANK

IL-13 & IL-13R (STAT6)

CD40, CD30, RANK

CD40, CD30, RANK

* (Gain or Amplification), ** (Point mutations) (Deletions)

AP-1, c-JUN JUN-B47-49.

IL-13 IL-13 STAT661. O

O micro RNAs (miRNAs)

Biology of Hodgkin Lymphoma

1. Swerdlow SH, Campo E, Harris NL, et al. Classification of

factor PU.1, necessary for B-cell development is expressed

**A <13gr/dl <11.5gr/dl .

CRP (, , ..) 15,17.

PET Scan (Positron Emission Tomography)

2, , , . HL. (,), (), ().

sAg, anti-HCV, anti-HIV

6. Hodgkin. Ann-Arbor/ Cotswolds

Hodgkin Lymphoma: clinical and laboratory findings and staging procedures

1. Grufferman S, Delzell E. Epidemiology of Hodgkins disease.

and alterations during ABVD chemotherapy: Correlation

* GHSG: 1/3 (0.33) ,

HD14 (16-60 16-75 HD10, HD11).

7F, H7U, H8F, H8U 10- 8-

36 Gy vs. 20 Gy vs. RT: p<0.001

10 97% 92% (p=0.001) -

3). , 2 ABVD . , , EORTC

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(interim) PET-Scan, 163 / 2- FFTF 94%

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