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R o m a n i a n

J o u r n a l

o f

O n c o l o g y & H e m at o l o g y
Nr. 1/ Vol. II/ 2014
Revist publicat sub egida
Societatea naional de oncologie medical din romnia; societatea romn de hematologie;
asociaia romn pentru studiul durerii; Societatea Romn de Cancer Vasile Pcurar

Chief Editor
Dr. Valentin Rdoi

Senior Editors
Prof. Dr. Florin Bdulescu (Universitatea de Medicin i Farmacie Craiova, Craiova, Romnia)
Prof. Dr. Anca Roxana Lupu (Universitatea de Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Lucia Stnculeanu(Universitatea de Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Simona Mihuiu (Universitatea de Medicin i Farmacie Oradea, Oradea, Romnia)
Cerc. St. Gr. I. Dr. Grigorescu Alexandru (Institutul oncologic Prof. Dr. Alexandru Trestiorean, Bucureti, Romnia)

Romanian Editorial Board

Prof. Dr. Oltean Galafteon (Universitatea of Medicin i Farmacie Trgu Mure, Trgu Mure, Romnia)
Prof. Dr. Ljubomir Petrov (Universitatea of Medicin i Farmacie Iuliu Haieganu, Cluj-Napoca, Romnia)
Prof. Dr. Ioni Hortensia (Universitatea of Medicin i Farmacie "Victor Babe" , Timioara, Romnia)
Prof. Dr. Ctlina Poian(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Monica Dragomir(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Coriu Daniel (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Anca Coli (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Horia Bumbea (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Elena Copaciu (Universitatea of Medicin i Farmacie Carol Davila, Bucureti, Romnia)
ef Lucrri Dr. Laura Mazilu (Facultatea de Medicin, Universitatea Ovidius, Constana, Romnia)
ef Lucrri Dr. Coli Andrei (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Cristian Silviu Voinea(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Asist. Univ. Mircea O. D. Lupusoru (University of Medicine and Pharmacy Carol Davila; Director Medical - Spitalul de Psihiatrie Titan Dr. C-tin Gorgos)
Asist. Univ. Gabriela Elena Lupusoru (University of Medicine and Pharmacy Carol Davila)
Asist. Univ. Dr. Carsote Mara-Laura (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Asist. Univ. Dr. Victor Gabriel Cltici (Universitatea of Medicin i Farmacie Carol Davila, Bucureti, Romnia
Asist. Univ. Dr. Trandafir Maria Silvia (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Asist. Univ. Dr. Ioana Soare (Universitatea Titu Maiorescu, Facultatea de Medicin, Bucureti, Romnia)
Dr. Adrian Udrea (Medisprof, Cluj-Napoca, Romnia)
Dr. Radu Niculescu (Institutul Clinic Fundeni, Bucureti, Romnia)
Dr. Ana Maria Boeru (Asociaia Free of Pain, Bucureti, Romnia)
Dr. Anca Coli (Institutul Clinic Fundeni, Bucureti, Romnia)
Dr. Virgil Dinc (Asociaia Romn pentru Studiul Durerii, Bucureti, Romnia)

International Editorial Board

Prof. Dr. med. Anca-L. Grosu (Klinik fr Strahlenheilkunde, Universitt Freiburg, Freiburg, Germany)
Prof. Dr. Shibo Li (University of Oklahoma Health Sciences Center,Oklahoma City,USA)
Prof. Dr.Mariusz Z. Ratajczak (University of Louisville,Louisville,USA)
Prof. Dr. Arnold Ganser (Hannover Medical School, Hanover, Germany)
Prof.Dr. Saverio Bettuzzi (University of Parma Via Volturno,Parma, Italy)
Prof. Dr.Lodovico Balducci (Moffitt Cancer Center,Tampa,USA)
Prof. Dr. Leonard Wartofsky (Georgetown University School of Medicine,Washington, USA)
Prof. Dr. Robert Amato (Memorial Hermann Cancer Center,Texas, USA)
Prof Dr.Kevin R. Loughlin (Harvard University,Cambridge,USA)
Prof. Dr. Maureen Markman (Drexel University College of Medicine, Philadelphia, USA)
Prof. Dr.Stephen P. Hunger (University of Colorado School of Medicine, Colorado,USA)
Prof. Dr. M.W.M. van den Brekel (Academic Medical Center Amsterdam, Amsterdam, Netherlands)
Prof. Dr.M Sitki Copur (University of Nebraska Medical Center, Nebraska, USA)
Prof. Dr. Derek Raghavan (UNC School of Medicine, Levine Cancer Institute, Charlotte, NC, USA)
Prof. Dr. Richard J. Ablin (University of Arizona, Arizona, USA)
Prof. Dr. Florian Strasser (Cantonal Hospital St. Gallen, Switzerland)
Prof. Dr. Michel Rigaud (Scientific advisor - IRST, Meldola, Italy)
Associate Prof.Dr.Mishu Popa McKiver (Massachusetts General Hospital,Massachusetts, USA)
Assistant Prof. Dr. Alina Mihai (Univ Pittsburgh School Medicine, Pittsburgh, USA)
Assistant Prof. Dr. Doru Paul (Hofstra North Shore-LIJ School of Medicine,New York,USA)
Assistant Prof.Dr. Bruno Vincenzi (University Campus Bio-Medico,Rome, Italy
Assistant Prof.Dr. Elizabeta C. Popa (Weill Cornell Medical College,NY, USA)
Assistant Prof.Dr.Gabriela Oprea (Emory University, Atlanta,USA)
Dr. Wainer Zoli (Director of the Bioscience Laboratory, IRST, Meldola, Italy)
Dr. Ciprian Enachescu (Centre Hospitalier Lyon Sud, Lyon, France)
Dr. Javier Martn Broto (Son Espases Hospital,Palma de MallorcaSpain)
Dr. David Gmez Almaguer (Universidad Autnoma de Nuevo Len, Monterrey, Mxico)

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6
8
12

Editorial

2014: A look behind but also a look ahead [ro]

Radoi V.

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet? [en]
Popa M.A., Amy M., McCord A.M., Moran J., Quintero J., Carlos F., Santos C.F.

The Devilish Cycle of the Cancer: Circulating Tumor Cells

and Epithelial Mesenchymal Transition as Actors [en]
Barriere G., Zoli W., Rigaud M.

16

News

20

Calendar
Scientific Events [en]

30

Case Presentations
Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular
Lymphocytic Population in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient:
A Case Report [en]
Ghiuzeli C.M.

36

Editor's Choice
Selection [en]

46

Instructions for Authors

Editorial
6

2014: O privire napoi, dar i nainte [ro]

Opiuni actuale de consolidare a primei remisiuni n limfomul folicular:

Ne apropiem de terapia ideal [en]

Rdoi V.

Popa M.A., Amy M., McCord A.M., Moran J., Quintero J., Carlos F., Santos C.F.

12

Ciclul diabolic al cancerului: celule tumorale circulante si tranziia epitelial mezenchimal [en]

16

Nouti

20

Evenimente

Barriere G., Zoli W., Rigaud M.

Manifestri tiinifice [en]

30

Prezentri de Caz
Apariia temporar n snge , asociat cu Dasatinib, a unei populaii clonale de limfocite
mari granulare la un pacient cu leucemie acut limfoblastic Filadelfia-pozitiv [en]
Ghiuzeli C.M.

36

Alegerea Editorului din Literatur

Selecie [en]

48

Instruciuni pentru autori

Editorial

2014: A look behind but also a look ahead

2014: A look behind but

also a look ahead
2014: O privire napoi, dar i nainte
Valentin Rdoi
Editor-in-Chief Romanian Journal of Oncology and Hematology; University of Medicine and Pharmacy Carol Davila
Coresponding author: Valentin Rdoi
Email: valentin.radoi@mediasyscom.ro

ntotdeauna este util ca la sfritul unei perioade determinate de timp, fie aceasta un an sau un deceniu, s
privim n urm la ce s-a realizat i nainte la ce ar mai fi
necesar. Putem considera acest proces ca fiind asemntor unui studiu clinic care s-a terminat i este nevoie
s vedem i s nelegem rezultatele, dar i s le putem
stabili pe cele pentru perioada viitoare.
Conform revistei Science, cea mai mare realizarea
n domeniul oncologiei, dar i a tiinei n general,
din 2013, este imunoterapia n cancer. Aceasta a fost
dezvoltat de-a lungul mai multor decenii, folosind
propriul sistem imun al corpului n lupta mpotriva
cancerului (1,2).
n 2014, conform aceleiai reviste, genomul ntreg
al pacienilor va fi cerut din ce n ce mai mult de ctre
clinicieni cu scopul de a identifica tratamente pentru cancer printre altele. Totodat, unul dintre cele
mai citate articole din domeniul oncologiei din 2013,
conform Web of Science, descrie caracterizarea geonomic integrat a carcinoamelor endometriale,
rezultatele putnd duce la o reclasificare care va influena tratamentul adjuvant post-chirurgie (3). Important este i programul Marii Britanii de a secvenia
genomurile a 100.000 de pacieni pe parcursul urmtorilor 4 ani (4).
Printre tratamentele descrise n cele mai citate studii
clinice din baza Thompson Reuters se numr i procarbazina, lumustina i vincristina adjuvant n tumorile

Cite this article:

Radoi V., 2014: A look
behind but also a look
ahead. Rom J Oncol
Hematol. 2014; 2(1):6-7

oligodendrogliale anaplastice (5), cabozantinib n cancerul de prostat avansat (6), crizotinib n cancerul pulmonar ALK-pozitiv (7), ibrutinib (PCI-32765) n limfomul
de tip B refractar/recidivat (8) i trametinib n melanomul
metastatic BRAF-mutant (9).
n privina incidenei i prevalenei cancerului
n 2013 datele publicate pn la ora actual estimeaz 854.790 de noi tumori la brbai n 2013 i
805.500 la femei n SUA. Pe primul loc la brbai
se afl cancerul de prostat, urmat de cancerul
pulmonar i de cancerul de colon i de rect, iar la
femei pe primul loc se afl cancerul mamar urmat
de cancerul pulmonar i de cancerul de colon i de
rect (Fig. 1) (10).
Mortalitatea determinat de cancer n SUA este estimat la 306.920 de decese la brbai i 273.430 la femei. Pe primul loc la ambele sexe se afl cancerul pulmonar, urmat de cancerul de prostat la brbai i cel
mamar la femei (Fig. 2) (11). O list detaliat a incidenei
i mortalitii din SUA este disponibil n referin (12).
International Agency for Research and Cancer
(IARC) a publicat la sfritul lui 2013 datele privind
incidena, prevalena i mortalitatea la nivel global n
2012. Numrul de noi cazuri de cancer a crescut de
la 12.7 milioane la 14.1 milioane, iar mortalitatea a
crescut de la 7.6 milioane la 8.2 milioane (date pentru
2008; respectiv 2012). Cancerul mamar a prezentat o
cretere cu peste 20% a incidenei, dar i o scdere

Figure 1. Incidena

estimat a cazurilor de
cancer n 2013 n SUA.
Adaptat dup (10)

Radoi V.

Figure 2. Numrul de

decese provocate de
cancer n 2013 n SUA.
Adaptat dup (11)

Figure 3. Mortalitatea

n urma cancerului
mamar la femei n
Romnia. Adaptat
dup (14)

cu 14% a mortalitii. Totui, aceasta rmne cea mai

mare cauz a decesului la femei (13).
n ceea ce privete situaia din Romnia, voi prezenta doar datele furnizate de IARC pentru cancerul mamar: cea mai mare mortalitate a fost atins n
2005 (16.49 decese la 100.000 de femei), n 2010
mortalitatea scznd la 15.03 decese la 100.000 de
femei (Fig. 3) (14). Pentru celelalte tipuri de cancer, dar
i pentru ali parametri poate fi accesat referina (14).

innd cont de toate aceste realizri n domeniul oncologiei i hematologiei, dar i de importana noilor
tratamente, scopul Romanian Journal of Oncology i
Hematology n 2014 va fi, n continuare, prezentarea
celor mai importante aspecte ale celor dou domenii prin articole originale, articole de sintez (reviewuri) i prezentri de caz.
Conflicts of Interest/Conflict de Interese: none/
nici unul

Bibliografie
1. Mcnutt M. Cancer Immunotherapy. Science 2013; 342: 1417.
2. Fedorov VD, Themeli M, Sadelain M. PD-1 and CTLA-4Based Inhibitory Chimeric
Antigen Receptors (iCARs) Divert Off-Target Immunotherapy Responses. Sci. Transl. Med
2013; 5:215ra172.
3. Getz G, Gabriel SB, Cibulskis K, et al. Integrated genomic characterization of endometrial
carcinoma. Nature 2013; 7447 (497):67-73.
4. Areas to Watch in 2014. Science 2013; 342:1443.
5. van der Bent MJ, Brandes AA, Taphoorn MJB, et al. Adjuvant Procarbazine, Lomustine,
and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: LongTerm Follow-Up of EORTC Brain Tumor Group Study 26951. Journal of Clinical Oncology
2013; 3(31):344-350.
6. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in Patients With Advanced Prostate
Cancer: Results of a Phase II Randomized Discontinuation Trial. Journal of Clinical Oncology
2013; 4(31):412-419.
7. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus Chemotherapy in Advanced ALKPositive Lung Cancer. New England Journal of Medicine 2013; 25(368):2385-2394.
8. Advani RH, Buggy JJ, Sharman JP, et al. Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies.
Journal of Clinical Oncology 2013; 1(31):88-94.

9. Kim KB, Kefford R, Pavlick AC, et al. Phase II Study of the MEK1/MEK2 Inhibitor
Trametinib in Patients With Metastatic BRAF-Mutant Cutaneous Melanoma Previously
Treated With or Without a BRAF Inhibitor. Journal of Clinical Oncology 2013;
4(31):482-489.
10. American Cancer Society. Surveillance Research. [Internet] 2013 [cited on 27
February 2014]. Available online from: http://www.cancer.org/acs/groups/content/@
epidemiologysurveilance/documents/document/acspc-037114.pdf
11. American Cancer Society. Surveillance Research. [Internet] 2013 [cited on 27
February 2014]. Available online from: http://www.cancer.org/acs/groups/content/@
epidemiologysurveilance/documents/document/acspc-037115.pdf
12. Siegel R, Naishadham D, Jemal A. Cancer Statistics 2013. Ca:A Cancer Journal for
Clinicians; 2013. 1(63):11-30.
13. International Agency for Research and Cancer. Latest world cancer statistics. Global
cancer burden rises to 14.1 million new cases in 2012: Marked increase in breast cancers
must be addressed [Internet] 2013 [Cited on 27 February 2014]. Available online from:
http://www.iarc.fr/en/media-centre/pr/2013/pdfs/pr223_E.pdf
14. Breast cancer death rates, per 100,000 women [Internet] 2014 [Cited on 27 February
2014]. Available online from: http://humanprogress.org/f1/breast-cancer-death-rateswomen/1950/2010/Romania

Martie 2014

Editorial

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet?

Current First Remission

Consolidation Options For
Follicular Lymphoma:
Are We There Yet?
Opiuni actuale de
consolidare a primei remisiuni
n limfomul folicular:
Ne apropiem de terapia ideal
Mihaela A. Popa1, Amy M. McCord1, Josue Moran1,2, Jerome Quintero1, Carlos F. Santos1
1. Biovest International Inc., 8500 Evergreen Blvd. NW, Minneapolis, MN, 44533, USA
2. Emory University, 201 Dowman Dr., Atlanta, GA, 30322, USA
Coresponding author: Mihaela A. Popa
Email: mmckiver@biovest.com

Follicular lymphoma (FL), an indolent B-cell

lymphoma, is the most frequent subtype of
nodal lymphoid malignancies in Western Europe (1). Of the 73,700 non-Hodgkins lymphomas (NHLs) patients in the European Union
(EU) in 2008 (2), about 20% represented FL patients (3). The disease burden posed by FL has
increased steadily during the past decades, as
reflected by the raise in incidence rate from
2-3/100,000 during the 1950s to 5-7/100,000
currently (1). Concurrently, the median overall
survival of FL patients has increased steadily
with the introduction of more potent therapies, most notably the anti-CD20 monoclonal
antibody, rituximab (4), (5). Recent figures from
the Survival, Epidemiology and End Results
(SEER) program indicate a 5-year relative survival rate of 85.4% (%95CI: 84.6- 86.2) in adCite this article:
vanced stage FL patients (6). Despite its high
Popa M.A., McCord A.M.,
responsiveness to first line therapies, FL reMoran J., Quintero J.,
mains characterized by multiple relapses and
Santos C.F., Current First
Remission Consolidation
progressively shorter remissions with evenOptions For Follicular
tual development of resistance to subsequent
Lymphoma: Are We There
therapies and ultimate treatment failure in the
Yet?. Rom J Oncol Hematol.
later stages of disease.
2014; 2(1):8-11

Individualized treatment planning for FL is

essential and depends on the characteristics
of both the patient (e.g., age, symptoms,
comorbidity, preservation of future therapy
options) and the disease (e.g., stage, FL
international prognostic index [FLIPI] risk group,
sites of involvement, prior therapy, duration of
benefit from prior therapy). Current rituximabchemotherapy first line induction therapies are
highly effective in reducing tumour burden in
advanced-stage FL patients (7),(8), (9) and responding
patients can receive subsequent consolidation
therapy aiming to eradicate residual cancer
cells with the ultimate goal of curing the patient.
An ideal consolidation therapy agent should
be extremely safe, improve the duration of
remission, not impede the efficacy of future
therapies in cases in which these therapies
become warranted, and be complementary
to induction therapy to effectively eradicate
residual cancer cells that are likely to be resistant
to the agents used in induction therapy. Given
the median age at diagnosis of FL patients of
60-65 years old (10), the projected ageing of the
population in the Western world that will likely

Mihaela A. Popa, Amy M. McCord, Josue Moran, Jerome Quintero, Carlos F. Santos

render FL a morbidity burden of the elderly, the

essentially symptom-free status of FL patients
in first remission, and the quasi-chronic disease
status of FL, developing nontoxic therapeutic
approaches to extend remission remains highly
desirable. The consolidation options authorized
in the EU (i.e., rituximab maintenance,
radioimmunotherapy, and interferon alpha-2b)
demonstrate clinical benefit but pose substantial
safety risks and show no plateau in survival (8), (11),
(12), (13), (14)
. The current focus, therefore, necessarily
shifts to improving the safety in addition to the
efficacy of remission consolidation therapies in
order to extend the quality besides the duration
of remissions.
In current clinical practice, about 50% of the
FL patients who respond to first-line induction
therapy receive no consolidation therapy,
and the remainders receive mostly rituximab
maintenance (15). However, rituximab is not an
ideal agent for consolidation therapy because
it is used during induction therapy. Conceivably,
one potential mechanism of action by which
maintenance rituximab prolongs the remission
duration may be by reinducing remission in
patients with subclinical relapses rather than by
eradicating residual tumour cells after induction
therapy. Moreover, the development of nearly
universal rituximab resistance (16), (17), (18), (19)
suggests that resistant cells present in the original
tumor persist and cause progressive (rituximabresistant) disease (20). Therefore, agents used for
consolidation therapy should ideally be different
from those used in induction therapy and should
have a different mechanism of action because
residual tumour cells may be resistant to these
agents. The prolonged nature of the rituximab
maintenance also imposes unique tolerability
challenges, specifically a substantial risk for
both low-grade and high-grade infections and/
or viral reactivations (8). Therefore, a high unmet
need remains for additional therapeutic options
which can provide significant clinical benefit
with a greatly improved safety profile, and which
could therefore balance the benefit/risk ratio
associated with the currently available agents.
A novel autologous, active immunotherapeutic,
dasiprotimut-T, addresses this unmet medical
need by offering FL patients a nearly toxicityfree, highly effective and durable consolidation
therapy option (21), (22).
The variable regions of the B-cell receptor
(BCR) immunoglobulin (Ig) heavy and light
chains combine to form the unique antigen
recognition site of antibodies and contain
determinants, called idiotypes, that can
themselves be recognized as antigens. The
idiotypic determinants of the immunoglobulin
synthesized by a clonal B-cell cancer, such as FL,

are unique and can thus serve as tumor specific

antigens (28), as initially demonstrated in mice (29).
The BCR, composed of the cell distinct surface Ig
and associated Ig/Ig components, regulates a
critical and wide-ranging cell signaling pathway
critical for cell survival, tolerance, apoptosis,
proliferation, and differentiation of the B-cell
into antibody producing cells or memory B-cells.
The BCR forms an integral component of a B-cell
life cycle, allowing it to interact with antigens via
highly conserved structural domains and unique
hypervariable regions arising from somatic
hypermutation as part of the B-cell maturation
in the early stages of immune cell development.
These hypervariable regions arise from a nearly
random selection of Variable (V), Diversity (D)
and Joining (J) genes and render B-cells with
an antigen-recognition diversity of enormous
potential.
B-cell malignancies are composed of clonal
proliferations of cells synthesizing a single
antibody molecule with unique variable regions
in the heavy and light chains. Therefore, the
idiotypic determinants of the surface Ig of a B-cell
lymphoma can serve as a tumor specific marker
for the malignant clone for immunotherapeutic
development purposes. The tumor specificity
of the idiotype allows triggering of an immune
response that spares healthy B-cells and
other cells which lack the unique BCR of the
lymphoma. Therefore, not only would an
active immunotherapeutic specifically target
tumor cells, but would also target a receptor
critical to the tumor cells survival. Moreover,
a considerable amount of clinical and in vitro
evidence suggests that FL is particularly sensitive
to immunotherapy. The high spontaneous
remissions rates observed in FL patients (23),
(24)
, the graft-versus-lymphoma effect postallogeneic stem cell transplant demonstrated in
several lymphomas (25), the correlation between
survival and the gene expression signature of
tumor infiltrating non-malignant immune cells
(26)
, the intrinsic potential of FL tumor-infiltrating
TH-cells to elicit cellular immune responses
when tumor-associated immune suppression
is attenuated (27), and the high response rates
to anti-CD20 therapies together support this
proposition.
DasiprotimutT is an autologous lymphomaderived Ig idiotype-KLH [keyhole limpet
haemocyanin] conjugate active immunotherapy
product designed to stimulate an immune
response based on specific recognition of
the tumor specific antigen, the Id, which
leads to tumor cell lysis and elimination of
residual FL cells. This patient-specific protein
active immunotherapy product is produced
by heterohybridoma rescue fusion, where the
Martie 2014

Editorial

Current First Remission Consolidation Options For Follicular Lymphoma: Are We There Yet?

patients lymphoma cells are fused to a mouse

heteromyeloma cell in order to produce the
tumorspecific Ig idiotype protein. The outcome
of this process is the high fidelity, fully humanized
idiotype protein suitable for immunization, which
is conjugated to the highly immunogenic carrier
protein KLH and administered with granulocyte
macrophage colony-stimulating factor (GMCSF)
as a vaccine adjuvant in FL patients in first
complete remission.
Clinical studies to date demonstrated that
dasiprotimut-T comprises all the elements
delineating an ideal consolidation therapy
(30), (31), (32), (33), (34), (21)
. From a clinical outcomes
standpoint, dasiprotimut-T improves remission
duration and is highly safe and well tolerated.
In a phase 3 randomized, double-blinded,
controlled trial dasiprotimut-T demonstrated
a similar reduction in the risk of relapse
(HR = 0.58; 95%CI: 0.370, 0.960) to that of
rituximab maintenance (HR = 0.57; 95% CI:
0.44, 0.74(8)). Safety data collected over 19
years indicate that the most common treatment
emergent, vaccine related adverse events
were injection site reactions. Serious adverse
events were very uncommon and there were
no vaccine related deaths. Most importantly, as
an active immunotherapy selectively targeting
malignant cells, dasiprotimut-T does not induce
immunosuppression and spares patients from the
consequences of extended immunosuppression
or myelotoxic radiation exposure associated
with the use of current consolidation regimens
(8), (11), (35)
.
From
an
immunogenicity
standpoint,
dasiprotimutT induces nearly universal durable
and persistent memory CD4+ and CD8+ T-cell
responses to the vaccine antigen, which lead
to tumor lysis and elimination (30), (31), (32), (33), (34).

Moreover, because severe circulating B-cell

depletion post-rituximab therapy appears not to
impair T-cell priming (36), (37) and memory B-cells
may persist in lymphatic tissues and contribute
to priming of T-cells (38), (39), dasiprotimutTinduces
effective tumorspecific T-cell responses even
post-rituximab induction therapy (40). Therefore,
dasiprotimutT is complementary to current
induction regimens, and can effectively
eradicate residual cancer cells that are likely
to be resistant to the agents used in induction
therapy. Lastly, its immunostimulatory rather
than immunosuppressive mechanism of action
does not hinder the efficacy of future therapies.
To date, there are no new potential
consolidation therapy candidates for first line
remission in FL, despite of a large array of
promising immunotherapy strategies (e.g.,
PD-1 inhibitors and other immune checkpoint
inhibitors) or targeted strategies (e.g., signaling
pathways inhibitors, proteasome inhibitors)
being investigated as induction therapy
options.
Ongoing trials are attempting to establish
the ideal rituximab maintenance schedule
and duration, or are investigating the
combination between rituximab maintenance
and radioimmunotherapy consolidation. While
these efforts will unquestionably enhance the
clinical outcomes of these existing regimens, it
is unlikely they will provide solutions to the most
persistent shortcomings of prolonged anti-CD20
monoclonal antibody therapy: protracted B-cell
depletion and refractoriness development.
Dasiprotimut-T has the potential to change
the risk/benefit ratio of first line consolidation
therapies for FL from the currently acceptable
to desirable, and herald a new therapeutic
paradigm in FL.

Bibliography
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and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 6:vi59-vi63.
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and mortality in Europe in 2008. Eur J Cancer. 2010;46(4):765-81.
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4. Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New
treatment options have changed the survival of patients with follicular
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5. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, et al.
Improvement of overall and failure-free survival in stage IV follicular
lymphoma: 25 years of treatment experience at The University of Texas M.D.
Anderson Cancer Center. J Clin Oncol. 2006;24(10):1582-9.
6. Howlader N NA, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL,
Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ,
Cronin KA (eds). . SEER Cancer Statistics Review, 1975-2010 National Cancer
Institute. Bethesda, MD2013 [cited 2013].

10

7. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits

R, et al. Frontline therapy with rituximab added to the combination of
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
significantly improves the outcome for patients with advanced-stage
follicular lymphoma compared with therapy with CHOP alone: results of a
prospective randomized study of the German Low-Grade Lymphoma Study
Group. Blood. 2005;106(12):3725-32.
8. Salles GA, Seymour JF, Offner F, Lpez-Guillermo A, Belada D, Xerri L, et
al. Rituximab maintenance for 2 years in patients with high tumour burden
follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a
phase 3, randomised controlled trial. Lancet. 2011;377(9759):42-51.
9. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grnhagen U,
Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as
first-line treatment for patients with indolent and mantle-cell lymphomas:
an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet.
2013.
10. Rohatiner AZ, Lister TA. The clinical course of follicular lymphoma. Best
Pract Res Cl Ha. 2005;18(1):1-10.
11. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H,

Mihaela A. Popa, Amy M. McCord, Josue Moran, Jerome Quintero, Carlos F. Santos
et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab
tiuxetan compared with no additional therapy after first remission in
advanced follicular lymphoma. J Clin Oncol. 2008;26(32):5156-64.
12. Baldo P, Rupolo M, Compagnoni A, Lazzarini R, Bearz A, Cannizzaro R,
et al. Interferon-alpha for maintenance of follicular lymphoma. Cochrane
Database of Systematic Reviews 2010(1).
13. Witzig TE. Safety of Yttrium-90 Ibritumomab Tiuxetan
Radioimmunotherapy for Relapsed Low-Grade, Follicular, or Transformed
Non-Hodgkins Lymphoma. J Clin Oncol. 2003;21(7):1263-70.
14. van Oers MH, Kersten MJ. Treatment strategies in advanced stage
follicular lymphoma. Best practice \& research Clinical haematology.
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15. Flowers C, Taylor M, Hirata J, Dillon HH, Zelenetz AD, Hainsworth JD, et
al. Use of maintenance rituximab (R) in the United States following R-based
induction for follicular lymphoma (FL). J Clin Oncol. 2010;28:15s:Abs. No.
8100.
16. Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS,
Link BK, et al. Rituximab anti-CD20 monoclonal antibody therapy in nonHodgkins lymphoma: safety and efficacy of re-treatment. J Clin Oncol.
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17. McLaughlin P, Grillo-Lopez AJ, Link B. Rituximab chimeric anitCD20 monoclonal antibody therapy for relapsed indolent lymphoma:
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18. Rezvani AR, Maloney DG. Rituximab resistance. Best Pract Res Cl Ha.
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19. Witzig TE, Vukov AM, Habermann TM, Geyer S, Kurtin PJ, Friedenberg
WR, et al. Rituximab therapy for patients with newly diagnosed,
advanced-stage, follicular grade I non-Hodgkins lymphoma: a phase
II trial in the North Central Cancer Treatment Group. J Clin Oncol.
2005;23(6):1103-8.
20. van Meerten T, Hagenbeek A. Novel antibodies against follicular nonHodgkins lymphoma. Best Pract Res Cl Ha. 2011;24(2):231-56.
21. Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman
JP, et al. Vaccination with patient-specific tumor-derived antigen in first
remission improves disease-free survival in follicular lymphoma. J Clin
Oncol. 2011;29(20):2787-94.
22. Schuster SJ, Neelapu SS, Santos CF, Popa-McKiver MA, McCord
AM, Kwak LW. Idiotype vaccination as consolidation therapy: time for
integration into standard of care for follicular lymphoma? J Clin Oncol.
2011;29(36):4845-6.
23. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA,
et al. Long-term effect of a watch and wait policy versus immediate systemic
treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a
randomised controlled trial. Lancet. 2003;362(9383):516-22.
24. Horning SJ, Rosenberg SA. The natural history of initially untreated lowgrade non-Hodgkins lymphomas. New Engl J Med. 1984;311(23):1471-5.
25. Thomson KJ, Mackinnon S. Role of allogeneic transplantation in lowgrade lymphoma and chronic lymphocytic leukemia. Curr Opin Hematol.
2006;13(4):273-9.

26. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, et al.
Prediction of survival in follicular lymphoma based on molecular features of
tumor-infiltrating immune cells. New Eng J Med. 2004;351(21):2159-69.
27. Hilchey SP, Rosenberg AF, Hyrien O, Secor-Socha S, Cochran MR, Brady
MT, et al. Follicular lymphoma tumor-infiltrating T-helper (TH) cells have
the same polyfunctional potential as normal nodal TH cells despite skewed
differentiation. Blood. 2011;118(13):3591-602.
28. Stevenson GT, Stevenson FK. Antibody to a molecularly-defined antigen
confined to a tumour cell surface. Nature. 1975;254(5502):714-6.
29. Lynch RG, Graff RJ, Sirisinha S, Simms ES, Eisen HN. Myeloma
proteins as tumor-specific transplantation antigens. P Natl Acad Sci USA.
1972;69(6):1540-4.
30. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R.
Introduction of Immune Respones in Patients with B-Cell Lymphoma Against
the Surface-Immunoglobulin Idiotype Expressed by Their Tumors. New Engl
J Med. 1992;327(17):1209-15.
31. Nelson EL, Li X, Hsu FJ, Kwak LW, Levy R, Clayberger C, et al. Tumorspecific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell,
non-Hodgkins lymphoma. Blood. 1996;88(2):580-9.
32. Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, et al.
Tumor-Specific Idiotype Vaccines in the Treatment of Patients With B-Cell
Lymphoma---Long-Term Results of a Clinical Trial. Blood. 1997;89(9):312935.
33. Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R,
et al. Complete molecular remissions induced by patient-specific vaccination
plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat
Med. 1999;5(10):1171-7.
34. Neelapu SS, Gause BL, Nikcevich DA, Schuster SJ, Winter J, Gockerman JP,
et al. Phase III randomized trial of patient-specific vaccination for previously
untreated patients with follicular lymphoma in first complete remission:
protocol summary and interim report. Clin Lymphoma. 2005;6(1):61-4.
35. Hagenbeek A, Radford JA, Van Hoof A, Vitolo U, Rohatiner AZ, Salles G,
et al., editors. 90Y-Ibritumomab Tiuxetan (Zevalin) Consolidation of First
Remission In Advanced-Stage Follicular Non-Hodgkins Lymphoma: Updated
Results After a Median Follow-up of 66.2 Months From the International,
Randomized, Phase III First-Line Indolent Trial (FIT) In 414 Patients. American
Society of Hematology Annual Meeting; 2010; Orlando, FL: Blood.
36. Qin Z, Richter G, Schuler T, Ibe S, Cao X, Blankenstein T. B cells inhibit
induction of T cell-dependent tumor immunity. Nat Med. 1998;4(5):627-30.
37. Gajewski TF, Pinnas M, Wong T, Fitch FW. Murine Th1 and Th2 Clones
Proliferate Optimally in Response to Distinct Antigen-Presenting Cell
Populations. J Immunol. 1991;146(No.6):1750-8.
38. Schrder C, Azimzadeh AM, Wu G, Price JO, Atkinson JB, Pierson RN.
Anti-CD20 treatment depletes B-cells in blood and lymphatic tissue of
cynomolgus monkeys. Transpl Immunol. 2003;12(1):19-28.
39. Kneitz C. Effective B Cell Depletion with Rituximab in the Treatment of
Autoimmune Diseases. Immunobiology. 2002;206(5):519-27.
40. Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, et
al. Vaccine-induced tumor-specific immunity despite severe B-cell depletion
in mantle cell lymphoma. Nat Med. 2005;11(9):986-91.

Martie 2014

11

Editorial

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors

The Devilish Cycle of the Cancer:

Circulating Tumor Cells and Epithelial
Mesenchymal Transition as Actors
Ciclul Diabolic al Cancerului:
Celule Tumorale Circulante i
Tranziia Epitelial-Mezenchimal
Guislaine Barriere, Wainer Zoli, Michel Rigaud
IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
Coresponding author: Michel Rigaud
michel.rigaud@yahoo.fr

Keywords:
EMT, Circulating Tumor Cells, Mesenchymal cells, Cancer stem cells, Metastasis

Cite this article:

Barriere G, Zoli W, Rigaud
M, The Devilish Cycle of
the Cancer: Circulating
Tumor Cells and Epithelial
Mesenchymal Transition as
Actors. Rom J Oncol
Hematol. 2014; 2(1):12-14

12

Breast cancer remains one of the major causes

of death in women worldwide. This cancer related death arises from tumor metastasis to secondary sites. A critical event for cancer metastasis
to occur is that a subpopulation of malignant cells (tumor initiating cells) has to acquire the ability to migrate and to invade a metastatic niche
via blood. Such a role can be assigned at least
to some circulating tumor cell (CTC) subpopulations. Epithelial mesenchymal transition (EMT)
supports the mobilization of primary tumor cells
which get involved with tumor progression.
EMT is a normal and reversible process which
is implicated in embryological steps like gastrulation, organogenesis of heart, musculoskeletal
system and the peripheral nervous system. More
recently, its role in diseased states was delineated, particularly during primary tumor metastasis (1). However, the two types are not superimposed. Not all steps described in developmental
EMT are necessary for the invasive phenotype to
be established and a partial EMT is sufficient to
give rise to initiating tumor cells at least in breast
carcinoma. One way to fight cancer would be to
find therapeutic agents that can reverse EMT or
eliminate mesenchymal and stem cancer cells
from the blood.
Before addressing CTC, we shall consider
events that support cancer EMT. Transforming

growth factor (TGF) is an essential EMT inducer. When TGF binds to its receptors, activation
of kinase functions leads to phosphorylation of
smad-2 and 3 which form a complex with smad-4
translocated from the cytoplasm to the nucleus.
The latter interacts with gene expression activators and repressors. TGF regulates EMT genes
through smad pathway (2). EMT converts polarized epithelial cells with cobblestone structure to
individual, motile spindle cells (3). The transition
leads to reduction of cell-cell contacts, (adherens junctions) transcriptional repression of Ecadherin expression, degradation of cell-matrix
adhesions, and rearrangement of the actin cytoskeleton. Lack of E-cadherin expression is one of
the defining features of invasive mesenchymal
cancer cells. Decreased E-cadherin expression is
often associated with inappropriate expression
of N-cadherin (4).
The reality seems more complex as partial
EMT leads to an intermediate phenotype, where
some characteristics of epithelium are retained,
but features of mesenchymal cells also appear (5).
In fact this concept is corroborated by detection
in cancer patient blood of the CTC subpopulations with mixed characteristics (6). Moreover, in
a model of an EMT decision network -(miR-34/
SNAIL) coupled with (miR-200/ZEB)-, Lu et al. explained the existence of a partial EMT state or

Guislaine Barriere, Wainer Zoli, Michel Rigaud

Figure 1. Devilish cycle of cancer and EMT

hybrid epithelial/mesenchymal phenotype (7).
They showed that the (miR-200/ZEB) loop has
three steady states: epithelial (high miR-200, low
ZEB), mesenchymal (low miR-200, high ZEB) and
partial EMT (medium miR-200, medium ZEB). The
situation becomes even more complicated as
mesenchymal cells are endowed with stemness
characteristics. Finally among CTC subpopulations we can find: epithelial, epithelial-mesenchymal, mesenchymal and mesenchymal stem cells.
These subpopulations are not strictly distinct
as there is a continuum between their different
stages. At the end of this EMT, the reverse process, mesenchymal-epithelial transition (MET)
will transform mesenchymal-stem cancer cells to
epithelial -stem cancer. Cells with mesenchymal
characteristics have a poor capacity to proliferate but when again acquiring the epithelial status
they will be able to develop a relapse in a metastatic niche. So a real devilish cycle of cancer
invasion becomes established through CTC subpopulations. The following scheme summarizes
this paradigm.

Many publications deal with CTC. They were

first described in 1869 by Ashworth (8). Research on this topic started again with the development of the CellSearch system able to numerate
foreign entities in the blood of cancer patients
(Veridex, Warren, New Jersey, USA). The methodology is based on the capture of the CTC
by EpCam antibody, the antigen being not expressed by blood cells. Until now, the number
of detected cells was used to set the prognostic of the cancer disease. Observed discrepancies between published CTC analysis methods
demonstrate that a gold standard method is
still missing (9). New improvements are ongoing. Generally the detection of CTC is based
on a blood volume sample from 7 to 30 ml.
Due to the Poisson statistics many false negative results can be alleged. The development of
Seldinger device overcomes this gap (10). When
CTC capture will be considered as perfect,
many other problems still have to be solved.
It is mandatory to define biochemical markers
able to characterize CTC subpopulations. We
Martie 2014

13

Editorial

The Devilish Cycle of the Cancer: Circulating Tumor Cells and Epithelial Mesenchymal Transition as Actors

cannot be satisfied with solely epithelial markers as the previously described EMT endows
cells with different phenotypes. They may or
may not include EpCam expression. Thus to
validate the use of CTC analyses and their applications in clinical settings, reworking in our
mind thinking is absolutely necessary. How to
develop a gold standard method? How to establish the correlation between this type of analyses, clinical following and therapy efficacy?
Can pathological EMT studies support discovery of new drugs leading to the breakdown
of cancer residual disease? Finally, our major

goal might be to interrupt the devilish cycle of

cancer recurrence.
Epithelial cells (cobble stone structure) from
primary tumors become motile mesenchymal
cells (spindle cells) and by shedding, invade blood. They are endowed with stemness features:
mesenchymal cancer stem cells (CSC). After extravasation, mesenchymal CSC overrun a niche
leading to metastasis. From the latter a new cycle of EMT can arise.
Conflicts of Interest/Conflict de Interese: none/nici
unul.

Bibliography
1. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell
Biol, 2003, 15(6): 740-746.
2. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions
during embryogenesis and cancer progression. Cancer Sci. 2007, 98(10):1512-1520.
3. Savagner P. Leaving the neighborhood: molecular mechanisms involved during epithelialmesenchymal transition. Bioessays. 2001, 23(10): 912-923.
4. Hazan RB, Qiao R, Keren R, Badano I, Suyama K. Cadherin switch in tumor progression. Ann N
Y Acad Sci. 2004, 1014: 155-163.
5. de Herreros AG, Peir S, Nassour M, Savagner P. Snail family regulation and epithelial
mesenchymal transitions in breast cancer progression. J Mammary Gland Biol Neoplasia. 2010,
15(2):135-147.
6. Barrire G, Riouallon A, Renaudie J, Tartary M, Rigaud M. Mesenchymal and stemness
circulating tumor cells in early breast cancer diagnosis. BMC Cancer. 2012, 12: 114.

14

7. Lu M, Jolly MK, Levine H, Onuchic JN, Ben-Jacob E. MicroRNA-based regulation of epithelialhybrid-mesenchymal fate determination. Proc Natl Acad Sci U S A. 2013, 110(45):1814418149.
8. Ashworth T. R. A case of cancer in which cells similar to those in the tumors were seen in the
blood after death. Australian Medicine Journal,1869,14, 146149.
9. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama
JW, Sleijfer S, Foekens JA. Anti-epithelial cell adhesion molecule antibodies and the detection of
circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009, 101(1): 61-66.
10. Saucedo-Zeni N, Mewes S, Niestroj R, Gasiorowski L, Murawa D, Nowaczyk P, Tomasi T, Weber
E, Dworacki G, Morgenthaler NG, Jansen H, Propping C, Sterzynska K, Dyszkiewicz W, Zabel M,
Kiechle M, Reuning U, Schmitt M, Lcke K. A novel method for the in vivo isolation of circulating
tumor cells from peripheral blood of cancer patients using a functionalized and structured
medical wire. . Int J Oncol. 201, 41(4):1241-1250.

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News

Rolul comisiei de tumor board n chirurgia oncologic

Rolul comisiei de tumor board

n chirurgia oncologic
Interviu cu prof. dr. Irinel Popescu, medic chirurg Spitalul OncoFort

De curnd , cel mai nou spital privat inaugurat n Capital a reunit

o echip de elit n chirurgia oncologic coordonat de ilustrul
prof. dr. Irinel Popescu. nc de la inaugurare, n spital s-a efectuat
o intervenie n premier de ctre ilustrul chirurg prof. dr. Irinel Popescu.

O dat cu succesul acestei dificile intervenii

chirurgicale, m-am simit la nceputul unui drum pe
care l-am ateptat de ceva vreme i pe care mi-l doresc cu ct mai multe mpliniri
...ne-a declarat la cald prof. dr. Irinel Popescu.
mai mare parte din cazuri n ceea ce privete debutul unei afeciuni hepatice.

Se spune c celulele ficatului se regenereaz.

Este cazul s lum fr a merge la medic medicamente pe care le vedem n reclame cu indicaia
c ajut la regenerarea celulelor ficatului?

Noutatea medical o reprezint operaia foarte

dificil efectuat unui pacient diagnosticat cu me
tastaz hepatic voluminoas cu punct de pleca
re colonic. Cu att mai dificil a fost faptul c pacient
ul era n programul de dializ de mai muli ani pentru
insuficien renal cronic, iar anestezia a fost cu
totul special pentru o astfel de operaie, riscul de
complicaii intra i post-operatoriu fiind foarte ridicat.
n fiecare lun sunt abordate peste 60 de intervenii
chirurgicale oncologice, cu nivel de complexitate ridicat, iar fiecare caz refuzat n spitalele de stat devine
o provocare pentru specialitii din cadrul spitalului.

Care sunt primele semne c ceva nu este n ordine

cu ficatul nostru i ar trebui s mergem la medic?
Un semn important este oboseala, tradus prin
capacitate mai redus de efort, nevoia de a face
pauze mai dese i tendina la somnolen. Se pot
aduga balonri, greuri, dureri n aria de proiecie
a ficatului (hipocondrul drept).

Setul curent de analize pe care ar trebui s le

facem fiecare anual este suficient pentru depistarea afeciunilor hepatice?
De regul, da. Transaminazele, bilirubina, gamaglutamil-transpeptidaza sunt edificatoare n cea

16

Nu exist nici un medicament care s ajute cu

adevrat procesul de regenerare, de aceea recomand mult pruden n utilizarea medicamentelor
crora li se face reclam n acest sens.

De curnd efectuai intervenii chirurgicale complexe n privat, ce tipuri de operaii ai efectuat?

Pn n prezent am efectuat rezecii de colon i
rect, gastrectomii totale, rezecii hepatice, operaii
pentru cancer de col uterin, operaii pentru cancer
de ovar, operaii pentru cancer de sn etc.

De multe ori, cazurile dificile (ex: cancerul)

sunt abordate multidisciplinar, avei cazuri pe
care le-ai tratat ntr-o comisie de tipul tumor
board? Care sunt avantajele unei astfel de
comisii?
Toate cazurile pe care le operez trebuie discutate
n tumor board pentru c numai astfel pacientul
poate s beneficieze de cel mai bun prognostic
de care poate beneficia n momentul de fa. A
opera fr o discuie a pacientului n tumor board
nseamn, n opinia mea, a-i reduce bolnavului
ansele terapeutice.

Ci pacieni din totalul celor care au nevoie pot

beneficia de transplant n timp util?
n prezent, n Romnia, cred c aproximativ 80%.

Nume autori

Martie 2014

17

News

Srbtorind succesul tomosintezei

SRBTORIND SUCCESUL TOMOSINTEZEI

Timpul, efortul i cheltuielile
investite pentru dezvoltarea
unei noi tehnologii nu ofer
garania c investiia va fi
eficient. Recompensa este
cu att mai mare cnd
aceste investiii se
amortizeaz i apar poveti
de succes aa cum se
ntmpl cu
SELENIA DIMENSION
sistemul de mamografie
digital cu tomosintez de
la Hologic (SUA).
Din 2008, de cnd a obinut marca CE, tomosinteza Hologic (SUA) a fost instalat n peste 50 de
ri i 48 de state din Statele Unite ale Americii.
Peste 1 milion de femei au fost vizualizate cu acest
sistem. SELENIA DIMENSION a fost citat n peste 60
de publicaii clinice, prezentri i abstracte.
Mult mai important, numrul n cretere de publicaii care arat c folosirea tomosintezei Hologic (SUA) mpreun cu imaginile 3D convenionale
conduc la o cretere semnificativ, cu pn la 27%,
a ratei de detecie a cancerului, n particular a cancerului minim invaziv, scznd n acelai timp rata
rechemrilor fals pozitive cu pn la 40%. n plus,
DOAR Hologic (SUA), prin SELENIA DIMENSION i
sistemul de stereotaxie Affirm, ofer posibilitatea
efecturii biopsiei de sn 3D. Toate acestea duc la
salvarea de viei printr-o diagnosticare precoce
i nceperea din timp a tratamentului.
2013 este al doilea an consecutiv cnd sistemele de mamografie digital Hologic (SUA)
ocup primele 3 locuri n topul satisfaciei utilizatorilor, iar sistemul cu tomosintez SELENIA

18

DIMENSION, premiul Best in KLAS. Acest premiu se acord celui mai performant echipament
medical i se bazeaz pe valori primite de la mii
de centre de diagnostic din Statele Unite i Canada.
Tomosinteza HOLOGIC i-a dovedit clinic superioritatea att prin numeroasele studii clinice
publicate att n Statele Unite, ct i n numeroase
ri din Europa sau alte pri ale lumii, dar i prin
particularitile tehnologice care o fac s fie cea
mai performant n acest moment.
Imagini de o calitate excepional pentru vizualizarea celor mai mici detalii.
Posibilitatea de a avea o achiziie rapid att
a imaginilor 2D de screening, ct i a celor 3D
tomosintez n doar 10 secunde i o singur compresie.
Caracteristici tehnice ergonomice, sofisticate,
dezvoltate special pentru confortul pacientului.
Din ce n ce mai multe femei sunt informate despre beneficiile tomosintezei i caut centre medicale care le pot oferi avantajele folosirii unei astfel
de tehnologii.
i n Romnia, Hologic se menine n top,
avnd n momentul de fa trei sisteme cu tomosintez instalate la Institutul Clinic Fundeni,
Institutul Oncologic Cluj i n Bucureti, la o
clinic privat.
HOLOGIC este o companie american, lider
mondial n mamografia digital, cu o cot de
pia de 52% la nivel mondial i peste 70% n
SUA n ceea ce privete vnzarea de mamografe
digitale.

n peste 60
Peste 50 de publicaii
40%
de
ri
cu
prezentri
Peste 1 imilion

cretere n detecia
cancerului mamar invaziv

sisteme n
utilizare

de femei examinate cu sistemul

cu tomosintez Hologic Selenia
Dimensions

27% Pn la

cretere 40% scdere

n detecia n rechemrile
total a fals pozitive
cancerului
de sn

ani de la obinerea
certicatul
u
i
CE
Prezena

n peste 60
Peste 50 de publicaii
de ri cu i prezentri

Singurul
sisteme n
utilizare

di
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pozi
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i
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aprobat
de FDA
Singurul
ani de la obinerea
certicatului CE

dispozitiv
Romnia prin:
aprobatDistribuit
dein FDA

S.C. Papapostolou SRL,Distribuit

os. Nicolae
Titulescu nr 1,
in Romnia prin:
S.C. Papapostolou
Nicolae
nr 1,
blbl A7,
sc B,SRL,
et 1,os.
ap 32,
sectorTitulescu
1, Bucureti,
A7, sc B, et 1, ap 32, sector 1, Bucureti,
tel/fax
021/321.22.23/4/5/6,
tel/fax
021/321.22.23/4/5/6,
mobil 0769/666.694, e-mail info@pmec.ro.
mobil 0769/666.694, e-mail info@pmec.ro.

Events

Scientific Events

Scientific Events
ONCOLOGY
ESTRO 33
04 - 08 April 2014
Vienna, Austria

It is my privilege and great pleasure as President of

ESTRO and Chair of the congress, to invite you to
ESTRO 33 that will take place in Vienna from 4 to
8 April 2014.
ESTRO 33 is the premier European event in
Radiation Oncology and will focus on new and
emerging developments in the field.
Since the foundation of ESTRO, more than 30
years ago, Radiation Oncology has fortunately
seen continuous change with virtually every
aspect of the basic science of our discipline and
of the clinical treatment drastically improving for
the benefit of patient care. In this context, ESTRO
33 will assist ESTROs recent Vision for 2020
statement that: Every cancer patient in Europe will
have access to state of the art radiation therapy,
as part of a multidisciplinary approach where
treatment is individualised for the specific patients
cancer, taking account of the patients personal
circumstances.
In line with the ESTRO Vision document, the ESTRO
33 Scientific Programme will aim to cover mainly
the following scientific topics.
The integration of new clinical and preclinical
evidence from biology, molecular/functional and
anatomic imaging in Radiation Oncology
The physical and biological optimisation of
radiation therapy

The use of new systemic agents together with

the delivery of high precision radiation therapy in
a safety aware environment
Combined-modality treatment using radiation
and either cytotoxic and/or targeted therapeutics
The use of high-precision radiotherapy used
with curative intent in patients with metastatic and
locally recurrent disease
New developments in radiation oncology that
further improve the safety of high-precision
radiotherapy
New approaches to adaptive radiotherapy
integrating novel developments in biology,
imaging, technology, and the assessment of
tumour response and patient outcome
The potential future use of novel biological
modifiers of tumour and normal tissue response
The development of validated predictive
models of treatment outcome based on complex
databases comprising clinical, biologic, genetic,
imaging, dosimetric and population data
Quality programmes, including clinical audit and
comprehensive safety systems in Radiation and
Clinical Oncology that maintain the principles of
providing the highest quality of patient care and
treatment in a safety-aware environment
Health services research in radiotherapy and
oncology, including the long term analysis of
changes in specialist staffing in the discipline, the
level of equipment, the appropriate implementation
of new technology, patient access to new treatment
approaches; together with the critical analysis of
these strategic developments using cost-benefit,
cost- utility and other means of health economic
review and health technology assessment
Clinical trials (phase 0, I, II, and III) in radiotherapy
and combined modality
Together, in sharing this patient-centered
objective, we will move the ESTRO Vision forward

Congresul Bienal de Cancer Mamar 14-17 mai 2014, Bile Felix

Congresul Bienal de Cancer mamar Bile Felix este deja tradiie, ajungnd la a X-a ediie. Receptat cu
mult interes de ctre participani, Bienala de sn a adus ntotdeauna n dezbatere probleme de actualitate privind diagnosticul i tratamentul cancerului mamar, contribuind personaliti medicale i tiinifice
de valoare naional i internaional. Multidisciplinaritatea, precum i posibilitatea de exprimare a
experienei clinice au condus, ediie dup ediie, la creterea numrului de participani.
Suntei invitai la a X-a ediie a Congresului Bienal de Cancer Mamar din 14-17 mai 2014, Bile Felix.
Informaii suplimentare putei gsi pe site-ul: www.oncobihor.ro.
Dr. Simona Mihuiu

20

and build what promises to be an event looking at

the challenges of the future.

The 7th International Conference on HPV,

Polyomavirus and UV in Skin Cancer
09 - 12 April 2014
Novara, Italy
The 7th International Conference on HPV,
Polyomavirus and UV in Skin Cancer will be held in
Novara, Italy, April 9-12 2014. It will bring together
leading scientists that will discuss the latest
research developments in UV & Virus related
skin cancer. Our goal is to serve as a forum for the
exchange of state-of-the-art information on human
papillomavirus (HPV) and polyomavirus (HPyV)
research and its future perspectives following
up on the proceedings of the 6th International
Conference of Berlin in 2012.

The European Congress on Head and Neck

Oncology (ECHNO 2014)
24 - 26 April 2014
Liverpool, United Kingdom
Welcome to the European Congress on Head
and Neck Oncology (ECHNO 2014), being held
at The ACC, Liverpool, UK from 24-26 April 2014.
An emphasis has been placed on addressing the
need for a multidisciplinary approach to facilitate
cooperation between the various clinical and
research specialties involved in the management
of head and neck cancer.
ECHNO 2014 will provide you with the latest
research and techniques in the ongoing effort
to improve the lives of patients everywhere. The
Congresss stellar scientific programmme will
feature experts from around the world, who will
facilitate stimulating debates about the most
controversial topics in Proton Therapy, Robotics
and Transoral Laser.
The compelling, challenging ECHNO 2014
programme will keep you busy by day. In the
evening, youll have the opportunity to explore the
historic city of Liverpool, famous around the world
as a musical and entertainment hub.
The congress venue is centrally located which will
allow you easy access to all the best attractions
that Liverpool has to offer. Join colleagues and
friends for three days of debates, discussions and
collaboration at ECHNO 2014.

The 15th World Congress

for Cervical Pathology and Colposcopy
(IFCPC 2014)
26-30 May 2014
London, United Kingdom
The 15th World Congress for Cervical Pathology
and Colposcopy (IFCPC 2014) will promote the

best possible standards of Colposcopy around

the world with the goal of guaranteeing that
women everywhere receive excellent care. IFCPC
will feature structured training sessions that will
improve clinician competence, performance and
patient outcomes through educational activities
focused around the study, prevention, diagnosis,
and management of HPV and genital tract
diseases.
By placing the latest research and techniques at
the service of health care professionals on every
continent, the congress seeks to bridge the gap
between theory and practice.
The BSCCP and 32 National Societies represented
by the IFCPC, this congress will provide the perfect
forum for sharing international knowledge and
experience, dealing with core issues in cervical
pathology and colposcopy. Meet the best and
brightest minds working in the field at IFCPC
2014.

ASCO 50th Annual Meeting

30 May - 3 June 2014
Chicago, Illinois
Attendees of the 2014 Annual Meeting will
find cutting-edge scientific presentations and
comprehensive educational content.
The ASCO Annual Meeting brings together more
than 25,000 oncology professionals from a broad
range of specialties, making it an excellent venue
for exploring the theme of the Meeting Science
and Society.
Description of Session Types
The 2014 Annual Meeting, developed by the
ASCO 2013-2014 Cancer Education Committee
and Scientific Program Committee, is made up of
the following session types:
Education Sessions
Education Sessions offer interdisciplinary or
multidisciplinary explorations of focused areas
of clinical oncology. ASCOs Cancer Education
Committee determines topics and format for
these sessions that will best serve the educational
needs of Annual Meeting attendees. Particular
care is taken to ensure that these sessions
address issues including surgical, radiation, and
geriatric oncology; symptom management; health
services research; international perspectives; and
pathology, as appropriate.
Clinical Problems in Oncology Sessions
Clinical Problems in Oncology Sessions combine
the use of case-based panel discussion with
interactive keypad technology for audience
participation. These sessions are ticketed and
require an additional registration fee.
Meet the Professor Sessions
Meet the Professor Sessions enable interactive
discussion between attendees and recognized
experts in a variety of subspecialty fields. The
format is informal with an emphasis on a face-toface exchange with the expert. These sessions are
ticketed and require an additional registration fee.
Martie 2014

21

Events

Scientific Events

Core Sessions Track

The Core Sessions track highlights the latest
updates in science and clinical practice. Designed
to help busy oncologists streamline their Annual
Meeting experience, Core Sessions may include
such topics as controversies in a particular disease
site, personalized care, or new developments in
the field. The Cancer Education Committee has
designated one or more education sessions in
each track as Core Sessions.
Special Sessions
Special Sessions include the presentation of
Awards and Award Lectures as well as symposia
recommended
by
other
oncology-related
organizations, the Cancer Education Committee,
the Scientific Program Committee, and the ASCO
Board of Directors as being of particular interest,
importance, and relevance to Meeting attendees.
Plenary Session
The Plenary Session includes 15-minute didactic
presentations highlighting abstracts of scientific
research deemed to have the highest merit and
greatest impact on oncology research and practice.
Experts in the field will serve as Discussants to
place research findings into perspective. The
Plenary Session will take place on Sunday, June 1,
2014, 1:00 PM-4:00 PM.
Oral Abstract Sessions
Oral
Abstract
Sessions
include
didactic
presentations of abstracts representing important
clinical and translational research findings by topic
category. Presenting authors may use PowerPoint
slides to accompany their oral presentation.
Experts in the field (Discussants) are chosen to
provide comprehensive themed discussions of the
findings from predetermined abstracts.
Clinical Science Symposia
Clinical Science Symposia provide a forum for
science in oncology, combining didactic lectures on
a specific topic with the presentation of abstracts.
Experts in the field (Discussants) place studies in
the appropriate context based on the strength of
the evidence and critically discuss the conclusions
in terms of their applicability to clinical practice.
Highlights of the Day Sessions
Highlights of the Day Sessions invite expert
discussants to present key findings, put abstracts
into clinical context, and provide an overview of
the previous days oral abstract sessions.
Poster Discussion Sessions
Posters Discussion Sessions highlight selected abstracts
of clinical research in poster format. The posters are
grouped by topic and are on display for a specified
time, followed by a discussion session in which expert
Discussants comment on the research findings.
General Poster Sessions
General Poster Sessions include selected abstracts
of clinical research in poster format. The posters are
grouped by topic and are on display for a specified
time. The Annual Meeting will again include Trials
in Progress poster presentations within each track,
designed to facilitate awareness of open, ongoing
clinical trials of any phase.

22

Oncologic Imaging Course 2013

CT, MRI, PET/CT, and Interventions in Cancer
Patients: A Practical Approach
27 - 29 June 2013
Dubrovnik/Croatia
On behalf of the three course organisers Prof.Dr.
Christian Herold, Prof. Dr. Dr.h.c. Hedvig Hricak and
Prof. Dr. Dr.h.c. Maximilian F. Reiser as well as the
whole OIC team, we would like to cordially thank
you for your participation at this years Oncologic
Imaging Meeting, held from June 27-29, 2013, in
Dubrovnik/Croatia.
The scientific programme of the course was
focused on CT, MRI, PET/CT, and Interventions
in Cancer Patients: A Practical Approach and
attracted more than 120 participants from Europe,
the United States of America, Asia and Australia.
After the regular course, workshops in breast
imaging and advanced post-processing took
place.
We hope you have enjoyed the course and are
looking very much forward to welcoming you
again in 2014, when the meeting will again be held
in the beautiful city of Dubrovnik.

The International Symposium on Pediatric

Neuro-Oncology (ISPNO)
28 June - 02 July 2014
Singapore, Singapore

Dear Colleagues and Friends of the Pediatric

Neuro-Oncology Community,
It is with great honor that I invite you to the 16th
ISPNO meeting from 28 June 02 July 2014, which
will be held in conjunction with the 8th St. JudeVIVA Forum in Pediatric Oncology in Singapore for
the first time. Since the first ISPNO meeting in 1986,
this biennial scientific conference has witnessed
progress that was unimaginable in the 1980s. The
pace of discovery and our knowledge of biology,
treatment and late effects of pediatric CNS tumors
has increased dramatically but many challenges
remain, particularly in translating these advances
to clinical care in developing nations.
This year is the first time ISPN (International Society
of Pediatric Neurosurgery), the ESPN (European
Society of Pediatric Neurosurgery), and WFNS
(World Federation of Neurosurgical Societies)
have collaborated in developing themes and
content for multidisciplinary sessions aimed at

boosting participation from both regional pediatric

neurosurgeons and leaders in the international
pediatric neurosurgery community.
It is also the first time the Pediatric Radiation
Oncology Society (PROS), has formally joined our
International Advisory Board to lead opinions and
assist in the design of multidisciplinary sessions
during the main ISPNO meeting. We expect
this new emphasis to attract even more regional
and international pediatric radiation oncology
delegates. This meeting is expected to provide
a unique opportunity to showcase the latest
innovations in radiation oncology and diagnostic
imaging as these disciplines are essential elements
of therapeutic planning in patients with CNS
tumors.
ISPNO is the forum of choice for researchers from
North America and Europe to announce pediatric
neuro-oncology research results. The meeting
encompasses advances in molecular diagnostics
and classification, the chemotherapy of tumors
of the CNS in Phase III trials, results of trials of
investigational new agents from Phase I and II trials
and the latest in supportive care.
Professionals involved in the care of children and
adolescents are encouraged to benefit from this
valuable opportunity to engage with experts, gain
insights and establish new collaborations from the
enriching plenaries, poster program and more.
Join us in Singapore for an unforgettable meeting!
About ISPNO
The International Symposium on Pediatric NeuroOncology (ISPNO) is the major biennial global

meeting of the multi-disciplinary international

community of professionals involved in the
research, diagnosis, treatment and rehabilitation of
infants and children with brain tumors. ISPNO has
enjoyed consistent growth since its first meeting in
1986 with over 800 delegates drawn mostly from
oncology, neurosurgery and radiation oncology.
16th ISPNO in 2014 will mark the third meeting of
ISPNO in the Asian region, as well as the first time it
returns to Asia since the 2004 meeting in Japan.
Throughout the entire symposium, attendees
will engage in dialog regarding new surgical
treatments, innovative research and advances
in pediatric neuro-oncology in a dynamic and
interactive forum designed to significantly expand
the knowledge base of attendees and further
enhance overall patient care worldwide.
16th ISPNO in Singapore
Widely regarded as the leading conference
destination in Asia, Singapore offers a safe and
enriching experience in a bustling cosmopolitan
setting with countless culinary and cultural
experiences! Singapore is Asias leading medical
hub with a global reputation as a medical convention
and training center, a fast-growing basic and clinical
research hub and a center for regional referrals.
Held in Suntec Singapore Convention and
Exhibition Centre (Suntec Singapore), the 16th
ISPNO will showcase the leading international
advances in basic, translational and clinical research
and also recent advances in addressing the global
burden of pediatric central nervous system (CNS)
tumors.

HEMATOLOGY
The 9th Baltic Conference of Hematology 2014
(BCH 2014)
24 - 26 April 2014
Vilnius, Lithuania

Dear Colleagues and Guests,

It is my honour and great pleasure to welcome you
to the 9th Baltic Conference of Hematology on
behalf of the Lithuanian Society of Hematology.
Baltic Conferences of Hematology are held
every other year and have turned out to be not
just regional but also international forums for
professionals interested in the improvement and
development of hematological care.
The substantial progress has been made in
hematology during the last years, we experience
ever faster changes new technologies, new
medications, and therefore contacts between

colleagues are becoming more and more

important. Without any doubt, Baltic Conferences of
Hematology are a great opportunity to participate
in presentations and discussions of the most recent
advances in this field of medicine and also a great
opportunity to establish long-term international
collaboration. One special and traditional feature
of the Baltic Conferences of Hematology has been
an amusing and joyful feeling of being together. I
hope that we can also fulfil the demands of social
life here in Vilnius and offer you a pleasant time
to communicate and have fun after the scientific
sessions. I hope you will enjoy the beautiful
Lithuania with its ancient history, modern social life
and progressive economic development.
I would like to wish all of us a very stimulating,
interesting meeting, lots of useful bring-back ideas
and especially to get the message of friendship
and collaborating in promoting the advance in our
specialty and beyond.
With warm regards,
Arturas Slobinas
President of Lithuanian Society of Hematology
Martie 2014

23

Events

Scientific Events

The British Society For Hematology

54th Annual Scientific Meeting 2014 (BSH 2014)
Birmingham, United Kingdom
28 - 30 April 2014
Dear Friends and Colleagues,
It is a huge honour to be President of the BSH and to
introduce the 54th Annual Scientific Meeting. The
meeting will be held at the ICC which is located in
the heart of Birmingham. As many of you will know,
Birmingham is a vibrant, bustling, cosmopolitan
city and apparently boasts more miles of canal
than Venice!
I have always been passionate about Hematology
and have always felt it is a privilege to have a
career in such a fascinating speciality. Hematology
embraces so many different aspects of medicine
and I hope our meeting will reflect the breadth and
very essence of our practice as haematologists.
Throughout my career I have loved debate and the
controversies that surround progress. Often it is not
the data but how we interpret the data that matters
as we treat our patients. I hope this meeting will be
stimulating, challenging and full of friendly debate
and discussion.
Finally we all make great friends as we have pursue
our careers and our ASM is always the friendliest
of meetings so come to Birmingham to learn, to
discuss, to relax and to enjoy.

with a cosmopolitan sense of life. The historic

area shows in its buildings and monuments the
incredible heritage of this city, while its cultural and
modern attractions indicate an active and dynamic
city. The attendees to MLTD-2014 will be able to
enjoy an excellent scientific meeting in a warm,
hospitable and enchanting city.
The venue, the Palacio de Congresos de Valencia,
is conveniently located beside nice hotels and
amenities with easy public transportation to the
entire city.
We have prepared an exciting and integrated
meeting offering a unique programme which
covers the whole basic, translational and clinical
spectrum of thrombosis, platelets, coagulation,
fibrinolysis, haemostasis and vascular biology
with care and appreciation for your scientific and
personal enjoyment.

The 19th Congress

of the European Hematology Association
12 - 15 June 2014
Milan, Italy

The 23rd International

Congress on Thrombosis 2014
(ICT 2014)
14 - 17 May 2014
Valencia, Spain

The Congress Executive Committee, the Local

Organizing Committee and the Council of the
Mediterranean League Against Thromboembolic
Diseases take pleasure in welcoming you to the
23rd Biannual International MLTD Congress 2014
in Spain.
We have organized a meeting that brings the
best and most novel advances in thrombosis
and related sciences to attending delegates. We
have especially focused on fostering the needs
of younger attendants by stimulating scientific
exchange, oral presentations, awards and special
social functions.
I like to welcome you to Valencia, the beautiful
Mediterranean City that is home to our 2014
meeting. Valencia has a long-lived history since its
foundation as a Roman colony in 138 BC. It has the
flavour of ancient cultures and traditions together

24

After 12 years EHAs congress is returning to Italy.

Milan is one of Italys most fashionable cities and
holds several historic and artistic attractions, and a
congress center with excellent facilities and a great
location.
The Scientific Program Committee will invite
authors to submit abstracts to be considered for
inclusion in the scientific program as of January 1,
2014. Abstracts can be submitted via this website
and here you will find detailed instructions
regarding the submission procedures and the full
abstract submission guidelines.
The submission of an abstract constitutes a formal
commitment by the presenting author to present
the abstract (if accepted) orally or as a poster in
the session and the time assigned by the Scientific
Program Committee. We therefore recommend
that submitters of abstracts register for the
congress simultaneously with abstract submission.
The official congress registration website will also
open as of January 1, 2014. The strict deadline for
the submission of abstracts will be March 1, 2014.

Nume autori

Martie 2014

25

Events

Scientific Events

Conferina Abordarea
Multidisciplinar n Cancer n 2014
Cancerul este una dintre cele mai comune boli ale zilelor
noastre. Datoria unui medic oncolog nu este doar aceea de a-l
trata pe pacient, ci de a-l ghida spre o stare de spirit, de a-i oferi
sperana i ncrederea care s l vindece.
n fiecare zi un om bolnav de cancer poate nva
de la capt care este sensul vieii i al fericirii.
n fiecare zi un om care sufer de aceast boal
poate tri schimbarea unei viei noi i regsirea iubirii fa de sine, fa de cei din jur i fa de lume
aa cum este ea.
Un pacient de cancer care s-a vindecat este una
dintre minunile acelea cu care oamenii de rnd se
ntlnesc rar, dar prin care medicii oncologi, prin
priceperea profesional i nelegerea uman,
ajung la mplinire i aprofundarea caracterului i
comportamentului.
Procesul dureaz mult sau suficient ct ntre medic i pacient s se creeze o legtur. Din acest
motiv, la final, cnd constai c ai reuit, satisfacia
nu vine doar din vindecare n sine, ci din legtura
profund creat cu o alt fiin uman, creia i-ai
determinat cursul vieii.

Fiecare clip dup vindecare este un nceput

diferit i unic, iar medicul oncolog este cel
care elibereaz lumina n toate zilele care vor
urma.
Pacienii de care comunitatea medicilor oncologi
din cadrul conferinei Abordarea multidisciplinar n cancer n 2014 are grij sunt toi oamenii
obinuii peste care dm din ntmplare zi de zi. n
spatele unui Mulumesc! scurt se ascund oameni
care sufer de aceast boal, fie c i ntlnim la
colul strzii sau pe scara blocului.
Sunt oameni normali, dar care au o calitate n
plus, dezvoltat nu la cerere, ci din fora unui moment care te poate schimba.
Aceast calitate se numete voin, iar
specialitii oncologi sunt cei care ajut la modelarea i creterea sa o dat cu tratamentul.
Esena multidisciplinaritii cancerului a fost
concentrat de ctre Asociaia Medisprof, cu sprijinul Asociaiei Oncologilor Privai din Romnia i
Diasan n conferina Abordarea multidisciplinar
n cancer n 2014.
Aceast conferin adun laolalt specialiti oncologi, nutriioniti, psihologi clinicieni, farmaciti

26

i asisteni oncologici. De la sesiuni tiinifice precum Interdisciplinaritate i medicin personalizat

n Romnia, s privim spre viitor i pn la sesiuni
desprePersonalizarea n tumorile mamare incipiente operabile, participanii vor avea ocazia s
afle i s nvee informaii valoroase din domeniul
oncologic.

Pacientul nostru, prietenul nostru

Meseria de medic te pune n faa unor situaii
greu de povestit la masa de duminic. Un ntreg
tranzit de triri i sentimente nvlete atunci cnd
afli c cel mai bun prieten din copilrie sufer de
aceast boal.
Povara unei astfel de afeciuni poate fi atenuat
dac medicul care se ocup de caz tie s arate
c prietenia se poate nate din cele mai ciudate
situaii.

Iubete-i pacientul ca pe tine nsui

Pe lng sesiunile tiinifice care vor fructifica modernitatea tehnicilor medicale oncologice, punem
accent pe iubirea fa de pacient. tim c nu putei
pleca acas cu acest atribut, dar mai tim i c poi
nva s iubeti i c tot acest sentiment se nate din
grij.
Avem grij:
- s aplicm cele mai noi tendine din medicina
oncologic;
- s corelm toate disciplinele ce pot ajuta pacientul;
- s v oferim accesul la experienele medicale
ale unor somiti n domeniu;
- s v livrm cele mai puternice i pregnante viziuni asupra sistemului medical;
- s ajutm la construirea unei comuniti interdisciplinare 4 n 1: specialiti oncologi, asisteni
medicali, nutriioniti i psihologi clinicieni;
- de pacienii notri.
Suntem profesioniti, deci avem grij. Pe lng
grija transmis sentimental-afectiv, avem grija
profesional. mpreun avem grij, aplicm cele
mai moderne metode, cele mai noi idei de tratamente n cadrul tuturor disciplinelor.

Bojan Zaric

Cristian Moldovan

4 zile numai bune pentru tiin!

Cu siguran v ntrebai care sunt tematicile abordate anul acesta i care este lista complet a speakerilor care vor susine prezentri n cadrul conferinei.
Pentru nceput, v prezentm programul preliminar
al sesiunilor, care vor fi prezentate n dou limbi: limba englez i limba romn.
n paralel cu aceste sesiuni, n holul Hohe Rinne
Hotel & Spa Pltini, cele mai importante companii din domeniul farmaceutic vor fi prezente
n cadrul spaiului expoziional. Acolo vei avea
acces la cele mai noi informaii referitor la tratamentele existente pe pia dedicate pacienilor
oncologici.

Program conferin
Joi
14.00 18.00: Primire participani
19.00 22.00: Cin
Vineri
9.00 9.15: Deschiderea conferinei
Dr. Adrian Udrea, preedinte Asociaia Oncologilor
Privai din Romnia
Rolul i scopul manifestrii conferinei Abor
darea multidisciplinar n cancer n 2014
9.15 9.45: Dr. Rzvan Curc, ef Secie oncologie
Spitalul Judeean de Urgen Alba
Interdisciplinaritate i medicin personalizat
n Romnia: s privim spre viitor!
Tumorile pulmonare - interdisciplinaritate i
medicin personalizat
9.45 10.15: Asist. prof. dr. Bojan Zaric, MD, PhD,
Specialist in internal medicine - interventional pulmonology, Medical oncologist, Institute for Pulmonary Diseases of Vojvodina, Clinic for Thoracic
Oncology, Head, Clinical Trials Unit, Head, Department for Invasive diagnostics, University of Novi
Sad, Faculty of Medicine, Serbia
Advanced bronchoscopic techniques in diagnosis
and staging of lung cancer.
10.15 - 10.45: Prof. dr. Alina Mihai, Consultant
Radiation Oncologist, Clinical Assistant Professor,

Alina Mihai

Xavier Pivot

Univ Pittsburgh School of Medicine, Master of Science, Radation Physics, UPMC Beacon Hospital,
Dublin
Rolul radioterapiei ablative stereotactice n
tratamentul cancerului pulmonar - avantaje i
provocri
10.45 11.15: Gavin Lawler
11.15 11.45: Pauz de cafea
Tumorile mamare noi modaliti de abordare,
noi tehnici i rezultate recente
12.00 12.30: Prof. dr. Xavier Pivot, Centre Hospitalier Rgional Universitaire Hpital Jean Minjoz
Besanon
(subject to be defined by the speaker)
12.30 13.00: Dr. Cristian Moldovan, Praticien Hospitalier, Centre Henri Becquerel, Rouen, France
Personalizarea n tumorile mamare incipiente
operabile
13.00 13.20: Simpozion Zoladex: speaker :
dr. Cristina Cebotaru, Oncologie, Cluj-Napoca
Putem personaliza secvena terapeutic n cancerul de prostat rezistent la castrare?
13.20 13.40: Simpozion Faslodex: speaker:
dr. Cristina Oprean, Oncologie, Timioara
Dezvoltarea hormonoterapiei i impactul major
asupra calitii vieii pacientelor cu cancer de sn
14.00 16.00: Prnz
18.00 19.00: Cin
Smbt
Tumorile gastrointestinale tehnici moderne
intervenionale i de diagnostic
9.00 9.30: Dr. Adrian Ctinean, medic primar
interne-gastroenterologie, asist. univ. UMF ClujNapoca, Centrul Medical Diasan
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Martie 2014

27

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Nume autori

Martie 2014

29

Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population
in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient: A Case Report

Dasatinib-Associated Transient
Peripheral Blood Appearance of a
Clonal Large Granular Lymphocytic
Population in a Philadelphia-Positive
Acute Lymphoblastic Leukemia Patient:
A Case Report
Apariia Temporar n Snge, Asociat
cu Dasatinib, a Unei Populaii Clonale
de Limfocite Mari Granulare la
un Pacient cu Leucemie Acut
LimfoblasticFiladelfia-Pozitiv
Cristina M. Ghiuzeli
North-Shore University Hospital and Long Island Jewish Medical Center,
Hofstra North Shore-LIJ School of Medicine, Manhassett, NY, USA
Coresponding author: Cristina M. Ghiuzeli
cghiuzeli@nshs.edu

Abstract:
Keywords:

Cite this article:

Ghiuzeli C M, DasatinibAssociated Transient
Peripheral Blood Appearance
of a Clonal Large Granular
Lymphocytic Population in a
Philadelphia-Positive Acute
Lymphoblastic Leukemia
Patient: A Case Report. Rom
J Oncol Hematol. 2014;
2(1):30-34

30

Dasatinib, Sprycel, Large

Granular Lymphocytes,
Lymphocytosis,
Acute Lymphoblastic
Leukemia, Philadelphia
Chromosome

Dasatinib (Sprycel) is a potent Breakpoint Cluster Region-Abelson

(BCR-ABL) oral tyrosine kinase inhibitor which has been used in
the treatment of Philadelphia-positive hematological malignancies
such as Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic
Leukemia (ALL). Herein, we describe a case in which the continuous
administration of Dasatinib led, after two months, to the transient
appearance of a clonal, Natural-Killer (NK)-like T-cell population.
This was first detected by the presence of an increased white blood
cell count consisting of lymphocytes, and review of the peripheral
smear showed large granular lymphocytes. The lymphocytosis and
the associated leukocytosis resolved within three weeks without
any interventions while the patient continued Dasatinib. This paper
will review the current literature on this subject, which suggests
that Dasatinib-associated large granular lymphocytosis (LGL) is
associated with a superior disease response.

Ghiuzeli M. Cristina

Rezumat:
Cuvinte-cheie:
Dasatinib, Sprycel,
limfocite mari
granulare, leucemie
acuta limfoblastic,
cromozomul Filadelfia

Dasatinib (Sprycel) este un inhibitor oral extrem de eficient al tirozinkinazei Breakpoint Cluster Region-Abelson (BCR-ABL) folosit n
tratamentul tumorilor maligne hematologice, cum ar fi leucemia
cronic mieloid i leucemia acut limfoblastic. n acest articol
descriem un caz n care administrarea continu a Dasatinibului a
provocat dup dou luni apariia temporar a unei clone de celule
de tipul Natural-Killer (NK)-like T-cells. Aceast clon a fost iniial
detectat prin prezena unei limfocitoze periferice; revizuirea frotiului
de snge a artat o populaie de limfocite mari granulare. Limfocitoza
i leucocitoza asociat au revenit la normal n decursul a trei sptmni
fr nici o intervenie. n acest articol rezumm literatura curent
pe acest subiect, care sugereaz c limfocitoza granular cu celule
mari indus de Dasatinib este asociat cu rspunsuri superioare n
tratamentul tumorilor maligne hematologice.

Abbreviations:
BCR-ABL=Breakpoint Cluster Region-Abelson,
ALL=Acute Lymphoblastic Leukemia, CML=Chronic
Myeloid Leukemia, TKI=Tyrosine Kinase Inhibitor,
LGL=Large Granular Lymphocyte, TCR=T-cell receptor, WBC=White Blood Cells, PCR=Polymerase Chain Reaction, NK=Natural Killer cells, PCR=Polymerase
Chain Reaction, CMV=Cytomegalovirus, BAL= Bronchoalveolar Lavage

Introduction:
Tyrosine kinase inhibitors are a family of oral, smallmolecule drugs that are targeted against the oncogenic fusion protein BCR-ABL, which is formed when
the ABL gene on chromosome 9 joins to the BCR
gene on chromosome 22, leading to the characteristic t (9;22) known as the Philadelphia chromosome
(1-3). This is the pathognomonic translocation in
CML, but can also be found in 20% of adult ALL and
50% of elderly ALL patients (4).
The first generation BCR-ABL TKI is Imatinib (Gleevec), with second-generation BCR-ABL Dasatinib
(Sprycel), Nilotinib (Tasigna) and Bosutinib (Bosulif)
which are several orders of magnitude more potent
than Imatinib. Nilotinib, for example, is a close analog of Imatinib, but it has a 20-fold higher potency
for BCR-ABL kinase inhibition than Imatinib, whereas
Dasanitib has yet another 10-fold increased potency
compared to Nilotinib (5,6). In addition, novel kinase
and non-kinase targets have been described in these
TKIs, and Dasatinib in particular was developed as
an immunosuppressor with dual specificity against
BCR-ABL and SRC-kinases (7,8).
Dasatinibs unique SRC-kinase and TEC family
kinase activities are thought to contribute to its immunomodulatory properties, as these proteins play
a role in the signaling pathways of the T- and B-cell
receptors (7). One such immunomodulatory phenomenon that has been observed is the appearance of
Large Granular Lymphocytosis (LGL) in the peripheral blood of approximately 30% of patients treated

with this drug (9-14). Furthermore, the patients with LGL

were also noted to present an increased incidence
of autoimmune-mediated side effects such as pleural effusions, colitis, and fever (8,11,15).
In this paper, we describe the case of a Philadelphiapositive Acute Lymphoblastic Leukemia patient who
was treated with Dasatinib, developed LGL and ple
ural effusions, and had a favorable clinical response.

Case Presentation:
Mr. V.S. is a 73 year old male who initially presented
to his primary care physician with dyspnea on exertion and lower extremity edema. A complete blood
count done by his primary care physician revealed
a white blood cell count (WBC) of 50,000/ul (10%
neutrophils, 1% myelocytes, and 89% blasts), a hemoglobin concentration of 5.9 g/dl, and a platelet
count of 181,000/ul, and based on it he was referred
for hospital admission.
The blood chemistry data obtained on admission
were as follows: sodium of 139 mmol/L, potassium of
4.3 mmol/L, chloride of 103 mmol/L, carbon dioxide
of 24 mmol/L, blood urea nitrogen of 24 mg/dl and
a creatinine of 1.27 mg/dl. The liver function testing
showed a total protein of 7.1 g/dl, serum albumin of
3.7 g/dl, aspartate aminotransferase (AST/SGOT) of
40 U/L, alanine aminotransferase (ALT/SGPT) of 21
U/L, total bilirubin of 0.3mg/dl, and an alkaline phosphatase of 86 U/L. The lactate dehydrogenase level
was significantly elevated at 1056 U/L (normal range
is between 50 and 242 U/L), with a uric acid of 8.4
mg/dl. The coagulation profile showed an activated
partial thromboplastin time of 24.7 seconds, a prothombin time of 13.9 seconds with a corresponding
INR ratio of 1.23, a fibrinogen of 478 mg/dl and an
elevated D-dimer assay of 1067 ng/ml (normal range
is between 0 and 499 ng/ml).
The patient received packed red blood cell transfusions for the anemia which led to symptomatic
improvement. The physical exam was significant for
lower extremity edema bilaterally, with no lymphaMartie 2014

31

Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population
in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient

Figure 1

denopathy or hepatosplenomegaly. Computer tomography (CT) scanning of the chest/abdomen/pelvis showed a left lower lobe pneumonia which was
treated with intravenous antibiotics, but there was no
evidence of lymph node enlargement, mediastinal
masses, or hepatic/splenic enlargement.
A bone marrow biopsy was performed, which
showed a hypercellular marrow (up to 100% cellularity) with an extensive infiltrate of immature cells,
scattered erythroid precursors and megakaryocytes
with normal morphology. The flow cytometry studies
showed a lymphoblast population (78% of cells), positive for HLA-DR, CD38, (partial) CD34, CD19, CD10,
CD22, (partial) CD20, (partial) CD15 and negative for
CD13, CD 33, CD117 and surface kappa and lambda
light chain determinants. The blasts were positive for
TdT by immunofluorescence staining. The findings
were consistent with B-lymphoblastic leukemia. Chromosomal analysis showed an abnormal karyotype:
eleven out of twenty examined metaphases had the
t(9;22) Philadelphia (Ph+) chromosome, nine metaphases had a normal 46XY male karyotype, and one
of the eleven Ph+ metaphases had additional copies
of chromosomes 6, 8, 12, 14, 21 making up for a total
of 54 XY. Florescence in situ hybridization (FISH) was
also positive for BCR/ABL1 (9q34/22q11.2) rearrangement in 83.5% of cells.
The patient consented to be enrolled in a phase
II multi-institutional clinical trial of Dasatinib as a primary treatment in Ph+ ALL adults over the age of
50 (Cancer and Leukemia Group B, CALGB 10701,
NCT01256398). A pre-treatment Multiple-Gated
Acquisition (MUGA) scan showed a normal ejection
fraction of 60%. His induction course consisted of
continuous Dasatinib 140 mg orally daily in combination with Dexamethasone 10 mg/m2/day orally for
days 1-7, and given the good response on the day 15

32

bone marrow biopsy (less than 20% marrow blasts),

the patient continued treatment on single agent Dasatinib treatment.
After 20 days, the patient developed shortness of
breath, and a chest X-ray showed new bilateral pleural effusions. There was no change to his ejection
fraction on a trans-thoracic echocardiogram, and the
effusions were attributed to Dasatinib. He was treated
with the diuretic Furosemide, and due to persistence
of symptoms, Dasatinib was briefly interrupted and
the patient underwent a thoracoscopy which effusion drainage. The dose of his Dasatinib was resumed
at 100 mg orally daily, which he then tolerated well. A
day 30 bone marrow biopsy showed complete morphological remission as well as a normal karyotype,
46XY and FISH negative for BCR-ABL1.
As an outpatient, he continued on oral Dasatinib
100mg daily with Furosemide for residual lower extremity edema and small pleural effusions, and his
complete blood counts were drawn at weekly intervals. He was noted (after about two months from the
initiation of Dasatinib) to have an elevated WBC count
of 10.4 K/ul, with an absolute neutrophil number of
3400/ul, absolute lymphocyte number of 6200/ul
(normal range is between 1000/ul and 3300/ul), absolute monocyte count of 800/ul, 100/ul eosinophils
and 0 basophils. Peripheral smear showed an increased number of large granular lymphocytes, with no
blasts present. The hemoglobin was 10.8 g/dl, with a
platelet count of 306 k/ul. Peripheral blood was sent
for flow cytometry and it identified, by morphology,
42% lymphocytes and 36% large granular lymphocytes. The immunophenotype showed Natural-Killer
(NK)-like T cells (19% of cells) positive for CD2, CD3,
CD5, CD7, CD8, CD56, CD57 and TCR alpha/beta.
Natural killer cells were also present (10% of cells) and
T-cells, with decreased CD4 to CD8 ratio (CD4% was

Ghiuzeli M. Cristina

Figure 2

16, CD8% was 72, with CD4/8 ratio of 0.23 normal

range is between 0.90 and 3.60). Molecular studies
for T-cell receptor (TCR) gene rearrangement identified discrete bands in both TCR-beta and TCR-gamma
analysis, suggestive of a clonal T-cell population. The
patient had no lymphadenopathy, hepatosplenomegaly or dyspnea. As a result of a low-grade fever
(100.8 degrees Fahrenheit), blood cultures, urine cultures, chest x-rays and Cytomegalovirus (CMV) titer
via Polymerase Chain Reaction (PCR) were checked.
The CMV PCR titer was low-positive at 500; this was
monitored with no antiviral therapy, and it became
negative approximately two weeks later.
The patient was monitored clinically, and his lymphocytosis was noted to gradually decrease over the
course of three weeks to normal, and not to recur
despite the continued administration of Dasatinib
at the same dose. He achieved a deep disease response at six months of treatment, namely bone marrow molecular complete response as evidenced by
a negative BCR-ABL by Polymerase Chain Reaction
(PCR). He is currently on continuous maintenance
phase, which includes Dasatinib in addition to oral
Methotrexate, oral 6-Mercaptopurine and monthly
intravenous Vincristine and oral Dexamethasone,
and has maintained a bone marrow morphological
remission at a year and a half since diagnosis.

Discussions
Large Granular Lymphocytes (LGL) generally represent 10-15% of the circulating mononuclear cells in
adults, with most having an NK-cell phenotype (CD3-,
CD16+, CD56+) (9). A clonal increase in the number of
peripheral blood LGLs generally leads to the diagnosis of LGL Leukemia, an indolent lymphoproliferative
disorder that is clinically characterized by lymphocytosis, cytopenias (most commonly neutropenia and ane-

mia), hepatosplenomegaly, fever, and autoimmune

conditions (most commonly rheumatoid arthritis) (16).
LGL Leukemia, in the appropriate clinical setting (such
as severe neutropenia or anemia), requires treatment
with immunosuppressive agents, typically oral Methotrexate or oral Cyclophosphamide (17).
However, it has been recognized that both monoclonal and oligoclonal LGL expansions can occur
after allogeneic stem cell transplantation, and in the
setting of chronic viral infections (18). When present,
they are associated with long-term remission in leukemic patients (19). Similarly, LGL has been described in
around 30%-40% of leukemia patients on Dasatinib,
and its presence has been associated with increased
therapeutic response (12-14). In contrast to LGL leukemia, the lymphocytosis does not require any intervention, and it ceases once Dasatinib is discontinued,
though lymphocyte values can vary during treatment
(14)
. Similarly, in our patient, lymphocytosis developed
two months after Dasatinib treatment, but it decreased to normal values and remained in the normal
range after three weeks.
Mustjoki et. al. (12), in a comparative study of 55 leukemia patients treated with a TKI, showed that the
large granular lymphocytosis (LGL) is a phenomenon
that is unique to Dasatinib (present in 38% of patients), and is not observed in patients who were treated with Imatinib, Nilotinib or Bosutinib, though all
TKIs can lead to clonal expansions of memory cytotoxic T-cells (11). In patients who developed LGL, both
with an underlying diagnosis of CML and Ph+ ALL,
molecular responses obtained were superior to the
patients who did not have lymphocytosis (13,14). This
was seen in our patient, who obtained a complete
molecular response by bone marrow PCR about six
months after diagnosis, thus after the development
of the transient lymphocytosis and LGL.
Martie 2014

33

Case Presentations

Dasatinib-Associated Transient Peripheral Blood Appearance of a Clonal Large Granular Lymphocytic Population
in a Philadelphia-Positive Acute Lymphoblastic Leukemia Patient

However, the Dasatinib-induced lymphocytosis

has been implicated in the autoimmune-like adverse
events reported with this drug, namely lung manifestations (both pleural effusions and lung parenchymal
involvement), colitis, and fevers (13). In a study of 40
patients with CML treated on Dasatinib, 22.5% developed lung abnormalities attributable to Dasatinib;
pleural effusion fluid revealed lymphocyte-predominant exudates, and these findings were consistent
with pleural biopsy and Bronchoalveolar Lavage
fluid (BAL) analyses (8,15). Pleural fluid immunophenotyping done in another trial by Mustjoki et. al. in patients treated with Dasatinib who experienced pleural
effusions confirmed the presence of a clonal T-LGL
cell population (13). Our patient developed pleural
effusions prior to the appearance of lymphocytosis,
and temporary discontinuation of the Dasatinib as
well as thoracocentesis led to symptomatic improvement of dyspnea.
Another association with the clonal expansion of
NK/T-cells in Dasatinib treated patients has been
CMV reactivation. In the Mustjoki et. al. trial which
included 22 Ph+ ALL patients on Dasatinib with lymphocytosis, 9 patients had modest CMV reactivation,
with CMV genome load paralleling the degree of
lymphocytosis (13). This resolved without any antiviral
treatment, as it did in our patient. Also, CD4+ T-cell
counts were noted to be decreased, with an increase
in CD8+ T-cells, as seen in our patient (13,18).
Finally, it is important to highlight two more findings related to the Dasatinib-induced LGL process.
The first is that it appears that a significant number
of patients have clonal lymphocytes present at CML
diagnosis, and the clone size expands with the administration of Dasatinib, but not Imatinib, leading
to the observed peripheral blood lymphocytosis (20).

In the study population of 34 CML patients, (20 of

whom subsequently received Dasatinib and 14 were
given Imatinib), 83% had a clonal, BCR-ABL1 negative lymphocyte population, whereas clonal lymphocytes were seen in only 8% of healthy control patients
(20)
. In 69% of the cases, the clone found in follow-up
samples was identical to the one at diagnosis, supporting the observation that Dasatinib favors the expansion of this preexisting clone.
The second interesting finding comes from a recent study published by Mustjoki et. al. in which 55
Ph+ ALL patients on TKIs had blood samples drawn
at specified time points from drug intake (12). It appears that the fluctuation in lymphocyte counts is
associated with the timing of blood draws, and the
degree of lymphocytosis is dose-dependent, with
peak drug and lymphocyte levels at one to two hours
after drug intake, and with a rapid decline thereafter.
The authors conclude that the previously observed
lymphocytosis is merely a reflection of drug administration-related timing.
In our patient, the LGL lymphocytosis was shortlived, and it did not recur despite frequent blood
count monitoring, but Mustjokis study does raise the
issue of consistent monitoring of lymphocyte counts
at a constant time-interval from oral Dasatinib administration. In the future, complete blood counts with
differentials drawn precisely one to two hours after
Dasatinib should be followed in all patients. Based
on the degree of lymphocytosis at that time point,
drug dose intensification should be investigated in
clinical trials given the favorable clinical outcomes
seen in patients with lymphocytosis.
Conflicts of Interest/Conflict de Interese: none/
nici unul.

Bibliography
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BCR gene in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc Natl Acad
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2. Barrett J, Guimaraes A, Cullis J, et al: Immunological characterization of the tumor-specific
bcr/abl junction of Philadelphia chromosome positive chronic myeloid leukemia. Stem Cells 11
Suppl 3:104-8, 1993
3. Dhut S, Chaplin T, Young BD: BCR-ABL and BCR proteins: biochemical characterization and
localization. Leukemia 4:745-50, 1990
4. Ribera JM: Optimal approach to treatment of patients with Philadelphia chromosome-positive
acute lymphoblastic leukemia: how to best use all the available tools. Leuk Lymphoma 54:21-7,
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5. Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med
Chem 47:6658-61, 2004
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imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 110:40554063, 2007
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patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 39:1098-109, 2009
9. Valent JN, Schiffer CA: Prevalence of large granular lymphocytosis in patients with chronic
myelogenous leukemia (CML) treated with dasatinib. Leuk Res 35:e1-3, 2011
10. Kreutzman A, Juvonen V, Kairisto V, et al: Mono/oligoclonal T and NK cells are common in
chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood

34

116:772-782, 2010
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tyrosine kinase inhibitors. Leuk Lymphoma 52:668-79, 2011
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induced by dasatinib therapy. Leukemia 27:914-24, 2013
13. Mustjoki S, Ekblom M, Arstila TP, et al: Clonal expansion of T/NK-cells during tyrosine kinase
inhibitor dasatinib therapy. Leukemia 23:1398-405, 2009
14. Kim DH, Kamel-Reid S, Chang H, et al: Natural killer or natural killer/T cell lineage large
granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive
leukemia. Haematologica 94:135-9, 2009
15. Bergeron A, Rea D, Levy V, et al: Lung abnormalities after dasatinib treatment for chronic
myeloid leukemia: a case series. Am J Respir Crit Care Med 176:814-8, 2007
16. Zhang D, Loughran TP: Large granular lymphocytic leukemia: molecular pathogenesis,
clinical manifestations, and treatment. ASH Education Program Book 2012:652-659,
2012
17. Lamy T, Loughran TP, Jr.: How I treat LGL leukemia. Blood 117:2764-74, 2011
18. Kreutzman A, Ladell K, Koechel C, et al: Expansion of highly differentiated CD8+ T-cells or NKcells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia
25:1587-97, 2011
19. Mohty M, Faucher C, Vey N, et al: Features of large granular lymphocytes (LGL) expansion
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20. Kreutzman A, Juvonen V, Kairisto V, et al: Mono/oligoclonal T and NK cells are common in
chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood
116:772-82, 2010

Nume autori

ndrumar pentru examenul practic

n specialitatea ORL i chirurgie cervico-facial
Apariie: 2013
Autori: Prof. Dr. Romeo Clrau, Dr. Tiberiu Dimitriu, Dr. Daniela Safta
Coautori: Dr. Ileana Linaru i Dr. Loredana Mitran
Adresare: medici primari i specialiti ORL, chirurgi, studeni, rezideni
Numeroasele examene i concursuri
pe care trebuie s le susin fiecare
medic dup terminarea facultii
solicit din partea fiecrui cadru
medical o susinut i continu
documentare. n sprijinul acestora,
periodic s-au publicat diferite
materiale, ce au folosit la buna
desfurare a acestor examene.

n acest context, ne-am gndit s

venim n ajutorul colegilor mai tineri,
cu experiena noastr, acumulat
n decursul anilor, n activitatea
clinic, dar i n pregtirea pe care
noi nine a trebuit s o facem,
cnd am fost nevoii s susinem
diferite examene i concursuri.
Tematica, stabilit de minister,

pe specialitile cu profil
chirurgical, implic, obligatoriu,
o prob practic, cu diferite
operaii, ce trebuie susinut
i practicat de ctre candidat.
Prof. Dr. Romeo Clrau,
Dr. Daniela Safta,
Dr. Tiberiu Dimitriu

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Alegerea Editorului din Literatur

Editors Choice
Majoritatea acestor articole sunt disponibile online gratuit prin realizarea unei
cutri pe pubmed (www.pubmed.com) dup numele articolului, al primului
autor i al jurnalului sau prin cutarea google pentru coleciile de articole.

ONCOLOGy

Most of these articles are freely available by searching the Medline database
(pubmed.com) for the articles name, the first authors name and/or the journals
name. A Google search is useful for article collections that are recommended here.

Effect of Acute Exercise on Prostate Cancer Cell Growth

Helene Rundqvist et al.

Abstract
Physical activity is associated with reduced risk of several cancers, including aggressive prostate
cancer. The mechanisms mediating the effects are not yet understood; among the candidates are
modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels
of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise
include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that
the elevation of serum growth factors may be detrimental to prostate cancer progression into
malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum
on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals
performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained
before (rest serum) and after completed exercise (exercise serum). The established prostate cancer
cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals
had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a
31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice
caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect;
increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible
detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term
effects seem to add to the overall beneficial influence of exercise on neoplasia.
Citation: Rundqvist H, Augsten M, Strmberg A, Rullman E, Mijwel S, et al. (2013) Effect of Acute Exercise
on Prostate Cancer Cell Growth. PLoS ONE 8(7): e67579. doi:10.1371/journal.pone.0067579

Genetic Variants in Hormone-Related Genes and Risk of Breast Cancer

Tess Clendenen et al.

Abstract
Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants
(SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone
levels. However, the relationship observed between these genetic variants and breast cancer
risk has been inconsistent. We conducted a case-control study nested within two prospective
cohorts to assess the relationship between specific genetic variants in hormone-related genes
and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were
included in the study. We did not observe an association between potential functional genetic
polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and
rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the
risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect
on breast cancer risk.
Citation: Clendenen T, Zeleniuch-Jacquotte A, Wirgin I, Koenig KL, Afanasyeva Y, et al. (2013) Genetic
Variants in Hormone-Related Genes and Risk of Breast Cancer. PLoS ONE 8(7): e69367. doi:10.1371/
journal.pone.0069367

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A Gene Signature to Determine Metastatic Behavior in Thymomas

Yesim Gkmen-Polar et al.

Abstract
Purpose
Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection
have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic
accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour
and optimize patient management.
Methods
qRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multiinstitutional archival primary thymomas (n = 36). Gene expression levels were used to compute
a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for
metastases. The signature was validated in an independent multi-institutional cohort of patients
(n = 75).
Results
A nine-gene signature that can predict metastatic behavior of thymomas was developed and
validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasisfree survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis
(P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates
were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively.
The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka
stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models
evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the
only independent indicator of metastases (P = 0.036).
Conclusions
A nine-gene signature was established and validated which predicts the likelihood of metastasis
more accurately than traditional staging. This further underscores the biologic determinants of the
clinical course of thymoma and may improve patient management.
Citation: Gkmen-Polar Y, Cook RW, Goswami CP, Wilkinson J, Maetzold D, et al. (2013) A Gene
Signature to Determine Metastatic Behavior in Thymomas. PLoS ONE 8(7): e66047. doi:10.1371/
journal.pone.0066047

Interferon-Based Therapy Decreases Risks of Hepatocellular Carcinoma

and Complications of Cirrhosis in Chronic Hepatitis C Patients
Ching-Sheng Hsu et al.

Abstract
Background
Interferon-based therapy (IBT) has been the standard of care for hepatitis C virus (HCV) infection.
However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular
carcinoma (HCC) and cirrhosis-associated complications, and most included highly selected
patients.
Methods
This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000)
consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance
enrollees in 2000 (>23.7 million). Patients with newly detected HCV infections (n = 11,264) were
classified based on treatment and clinical outcomes. IBTs were defined as regimens that included
interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months.
The Cox proportional hazards models were used to estimate the hazard ratio (HR) and associated
confidence interval (CI) of HCC and cirrhosis-associated complications for IBT.
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Alegerea Editorului din Literatur

Results
The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among
those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT
during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.310.81; P = .004).
Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95%
CI, 0.220.91; P = .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.210.69; P = .001),
ascites (adjusted HR, 0.28; 95% CI, 0.140.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI,
0.440.91; P = .013) were significantly higher among patients who received IBT than those who did
not, after adjustment for associated factors.

ONCOLOGy

Conclusion
Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications
in patients with chronic HCV infection.
Citation: Hsu C-S, Huang C-J, Kao J-H, Lin HH, Chao Y-C, et al. (2013) Interferon-Based Therapy
Decreases Risks of Hepatocellular Carcinoma and Complications of Cirrhosis in Chronic Hepatitis C
Patients. PLoS ONE 8(7): e70458. doi:10.1371/journal.pone.0070458

Senescence and aging: the critical roles of p 53

ARufini et al.

Abstract
p53 functions as a transcription factor involved in cell-cycle control, DNA repair, apoptosis
and cellular stress responses. However, besides inducing cell growth arrest and apoptosis,
p53 activation also modulates cellular senescence and organismal aging. Senescence is an
irreversible cell-cycle arrest that has a crucial role both in aging and as a robust physiological
antitumor response, which counteracts oncogenic insults. Therefore, via the regulation of
senescence, p53 contributes to tumor growth suppression, in a manner strictly dependent
by its expression and cellular context. In this review, we focus on the recent advances on
the contribution of p53 to cellular senescence and its implication for cancer therapy, and
we will discuss p53s impact on animal lifespan. Moreover, we describe p53-mediated
regulation of several physiological pathways that could mediate its role in both senescence
and aging.
Citation: Oncogene (2013) 32, 51295143; doi:10.1038/onc.2012.640

Downregulation of miRNA-31 induces taxane resistance in ovarian

cancer cells through increase of receptor tyrosine kinase MET
TMitamura et al.

Abstract
Ovarian cancer is one of the most aggressive female reproductive tract tumors. Paclitaxel (PTX)
is widely used for the treatment of ovarian cancer. However, ovarian cancers often acquire
chemotherapeutic resistance to this agent. We investigated the mechanism of chemoresistance
by analysis of microRNAs using the ovarian cancer cell line KFr13 and its PTX-resistant derivative
(KFr13Tx). We found that miR-31 was downregulated in KFr13Tx cells, and that re-introduction of
miR31 re-sensitized them to PTX both in vitro and in vivo. miR-31 was found to bind to the 3-UTR
of mRNA of MET, and the decrease in MET correlated to higher sensitivity to PTX. Furthermore,
co-treatment of KFr13Tx cells with MET inhibitors sensitized the tumor cells to PTX both in
vitro and in vivo. In addition, lower levels of miR31 and higher expression of MET in human
ovarian cancer specimens were significantly correlated with PTX chemoresistance and poor
prognosis. This study demonstrated miR31-dependent regulation of MET for chemoresistance
of ovarian cancer, raising the possibility that combination therapy with a MET inhibitor and PTX
will increase PTX efficacy.
Citation: Oncogenesis (2013) 2, e40; doi:10.1038/oncsis.2013.3

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The N-factors in pancreatic cancer: functional relevance

of NF-B, NFAT and Nrf2 in pancreatic cancer
AArlt et al.

Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies, with an
overall life expectancy of 6 months. Despite considerable advances in the understanding of the
molecular mechanisms involved in the carcinogenesis of PDAC, the outcome of the disease was not
significantly improved over the last 20 years. Although some achievements in molecular-targeted
therapies have been made (that is, targeting the epidermal growth factor receptor by erlotinib), which
already entered clinical settings, and despite the promising outcome of the FOLFIRINOX trial, there
is an urgent need for improvement of the chemotherapy in this disease. A plethora of molecular
alterations are thought to be responsible for the profound chemoresistance, including mutations
in oncogenes and tumor suppressors. Besides these classical hallmarks of cancer, the constitutive
or inducible activity of transcription factor pathways are characteristic changes in PDAC. Recently,
three transcription factorsnuclear factor-B (NF-B), nuclear factor of activated T cells (NFAT) and
nuclear factor-E2-related factor-2 (Nrf2)have been shown to be crucial for tumor development
and chemoresistance in pancreatic cancer. These transcription factors are key regulators of a variety
of genes involved in nearly all aspects of tumorigenesis and resistance against chemotherapeutics
and death receptor ligands. Furthermore, the pathways of NF-B, NFAT and Nrf2 are functional,
interacting on several regulatory steps, and, especially, natural compounds such as curcumin
interfere with more than one pathway. Thus, targeting these pathways by established inhibitors
or new drugs might have great potential to improve the outcome of PDAC patients, most likely
in combination with established anticancer drugs. In this article, we summarize recent progress
in the characterization of these transcription-factor pathways and their role in PDAC and therapy
resistance. We also discuss future concepts for the treatment of PDAC relying on these pathways.
Citation: Oncogenesis (2012) 1, e35; doi:10.1038/oncsis.2012.35

A mechanism of resistance to gefitinib mediated by cellular

reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop
K EWare et al.

Abstract
Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung
tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop
resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed
non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered
them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to
previously observed resistance mechanisms including EGFR-T790M gate-keeper mutations and MET
amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279
and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1
(FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial
to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression
and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1
expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an
FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly
inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment
with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones.
Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel
autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are
initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable
additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired
resistance in EGFR-driven NSCLC.
Citation: Oncogenesis (2013) 2, e39; doi:10.1038/oncsis.2013.4
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Alegerea Editorului din Literatur

MicroRNAs in colorectal cancer stem cells:
new regulators of cancer stemness?
SCaruso et al.

ONCOLOGy

Abstract
Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called cancer
stem cells (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed
experimentally in various human cancers. Several studies have confirmed the existence of colorectal
CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression
of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which
are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of
biological functions, including development, cell proliferation, differentiation, metabolism and signal
transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness
of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have
begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent
advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding
the molecular mechanisms and the possible approaches for colorectal cancer therapy.
Citation: Oncogenesis (2012) 1, e32; doi:10.1038/oncsis.2012.33

A HormoneDNA Repair Circuit Governs the Response to Genotoxic Insult

Jonathan F. Goodwin et al.

Abstract
Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly
understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and
therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA
damage and promotes expression and activation of a gene expression program governing DNA repair.
Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and
resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase
catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated
DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR
function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these
studies identify the ARDNAPKcs circuit as a major effector of DNA repair and therapeutic resistance
and establish a new node for therapeutic intervention in advanced disease.
SIGNIFICANCE: The present study identifies for the first time a positive feedback circuit linking
hormone action to the DNA damage response and shows the significant impact of this process on
tumor progression and therapeutic response. These provocative findings provide the foundation
for development of novel nodes of therapeutic intervention for advanced disease.
Citation: Cancer Discov; 3(11); 118.

Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers

William R. Polkinghorn et al.

Abstract
We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair
genes that promotes prostate cancer radioresistance, providing a potential mechanism by which
androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant
prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of
DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of
AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq
and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent

40

direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen
demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen
treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate
that antiandrogen treatment results in decreased classical nonhomologous end-joining.
Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential
mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.
Citation: Cancer Discov; 3(11); 19.

Quantifying the natural history of breast cancer

K H XTan et al.

Abstract
Background
Natural history models of breast cancer progression provide an opportunity to evaluate and
identify optimal screening scenarios. This paper describes a detailed Markov model characterising
breast cancer tumour progression.
Methods
Breast cancer is modelled by a 13-state continuous-time Markov model. The model differentiates
between indolent and aggressive ductal carcinomas in situ tumours, and aggressive tumours of
different sizes. We compared such aggressive cancers, that is, which are non-indolent, to those which
are non-growing and regressing. Model input parameters and structure were informed by the 1978 1984 Ostergotland county breast screening randomised controlled trial. Overlaid on the natural history
model is the effect of screening on diagnosis. Parameters were estimated using Bayesian methods.
Markov chain Monte Carlo integration was used to sample the resulting posterior distribution.
Results
The breast cancer incidence rate in the Ostergotland population was 21 (95% CI: 1725) per
10000 woman-years. Accounting for length-biased sampling, an estimated 91% (95% CI: 8597%)
of breast cancers were aggressive. Larger tumours, 2150mm, had an average sojourn of 6 years
(95% CI: 316 years), whereas aggressive ductal carcinomas in situ took around half a month (95%
CI: 01 month) to progress to the invasive 10mm state.
Conclusions
These tumour progression rate estimates may facilitate future work analysing cost-effectiveness
and quality-adjusted life years for various screening strategies.
Citation: British Journal of Cancer (2013) 109, 20352043. doi:10.1038/bjc.2013.471

The cancer biology of whole-chromosome instability

P H GDuijf and RBenezra

Abstract
One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell
division (W-CIN), leads to aneuploidy. Although W-CIN is a hallmark of most cancers, mutations in genes
involved in chromosome segregation are exceedingly rare. We discuss an oncogene-induced mitotic stress
model that provides a mechanistic framework to explain this paradox. We also review the tumor-promoting
and tumor-suppressing consequences of W-CIN. Importantly, we do this in the context of cancer as a complex
systemic disease, rather than as a simple linearly progressing disorder that arises from a single abnormal cell
population. Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous
entities, such as the immune system and the tumor microenvironment. Distinct tissue-specific susceptibilities
to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed.
Citation: Oncogene (2013) 32, 47274736;
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Complete Genes May Pass from Food to Human Blood
Sndor Spisk et al.

HEMATOLOGY

Abstract
Our bloodstream is considered to be an environment well separated from the outside world and the
digestive tract. According to the standard paradigm large macromolecules consumed with food cannot
pass directly to the circulatory system. During digestion proteins and DNA are thought to be degraded
into small constituents, amino acids and nucleic acids, respectively, and then absorbed by a complex
active process and distributed to various parts of the body through the circulation system. Here, based
on the analysis of over 1000 human samples from four independent studies, we report evidence that
meal-derived DNA fragments which are large enough to carry complete genes can avoid degradation
and through an unknown mechanism enter the human circulation system. In one of the blood samples
the relative concentration of plant DNA is higher than the human DNA. The plant DNA concentration
shows a surprisingly precise log-normal distribution in the plasma samples while non-plasma (cord
blood) control sample was found to be free of plant DNA.
Citation: Spisk S, Solymosi N, Ittzs P, Bodor A, Kondor D, et al. (2013) Complete Genes May Pass
from Food to Human Blood. PLoS ONE 8(7): e69805. doi:10.1371/journal.pone.0069805

Fibrin Clot Structure and Platelet Aggregation

in Patients with Aspirin Treatment Failure
Ss Neergaard-Petersen et al.

Abstract
Background
Aspirin is a cornerstone in prevention of cardiovascular events and modulates both platelet
aggregation and fibrin clot formation. Some patients experience cardiovascular events whilst on
aspirin, often termed aspirin treatment failure (ATF). This study evaluated both platelet aggregation
and fibrin clot structure in patients with ATF.
Methods
We included 177 stable coronary artery disease patients on aspirin monotherapy. Among these,
116 (66%) had ATF defined as myocardial infarction (MI) whilst on aspirin. Platelet aggregation
was assessed by Multiplate aggregometry and VerifyNow, whereas turbidimetric assays and
scanning electron microscopy were employed to study fibrin clot characteristics.
Results
Enhanced platelet aggregation was observed in patients with ATF compared with non-MI patients following
stimulation with arachidonic acid 1.0 mM (median 161 (IQR 95; 222) vs. 97 (60; 1776) AU*min, p = 0.005)
and collagen 1.0 g/mL (293 (198; 427) vs. 220 (165; 370) AU*min, p = 0.03). Similarly, clot maximum
absorbance, a measure of fibrin network density, was increased in patients with ATF (0.48 (0.41; 0.52) vs. 0.42
(0.38; 0.50), p = 0.02), and this was associated with thinner fibres (mean SD: 119.727.5 vs. 127.831.1
nm, p = 0.003) and prolonged lysis time (552 (498; 756) vs. 519 (468; 633) seconds; p = 0.02). Patients with
ATF also had increased levels of C-reactive protein (CRP) (1.34 (0.48; 2.94) and 0.88 (0.32; 1.77) mg/L, p =
0.01) compared with the non-MI group. Clot maximum absorbance correlated with platelet aggregation (r =
0.310.35, p-values<0.001) and CRP levels (r = 0.60, p<0.001).
Conclusions
Patients with aspirin treatment failure showed increased platelet aggregation and altered clot
structure with impaired fibrinolysis compared with stable CAD patients without previous MI. These
findings suggest that an increased risk of aspirin treatment failure may be identified by measuring
both platelet function and fibrin clot structure.
Citation: Neergaard-Petersen S, Ajjan R, Hvas A-M, Hess K, Larsen SB, et al. (2013) Fibrin Clot
Structure and Platelet Aggregation in Patients with Aspirin Treatment Failure. PLoS ONE 8(8): e71150.
doi:10.1371/journal.pone.0071150

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Characteristics of chronic GVHD after cord blood transplantation

L F Newell et al.

Abstract
Most reports of chronic GVHD after cord blood transplantation (CBT) have utilized traditional
diagnostic criteria. We used traditional criteria and National Institutes of Health (NIH) criteria
prospectively to evaluate chronic GVHD in a cohort of 87 adult and pediatric recipients of single
or double unrelated CBT for treatment of hematologic malignancies. Fifty-four patients developed
traditionally defined chronic GVHD, for an estimated 2-year probability of 64%. Among 54 patients,
25 (46%) met the NIH criteria for persistent, recurrent or late acute GVHD at onset. Twenty-four
(44%) had overlap chronic GVHD, including one who presented initially with late acute GVHD, and
only seven (13%) had classic chronic GVHD, including one who also presented initially with late
acute GVHD. Among patients who successfully discontinued all systemic immunosuppression (SI),
the median time to discontinuation of corticosteroid treatment was 315 days (range 28977), and
the median time to discontinuation of all SI was 353 days (range 67977). Chronic GVHD diagnosed
by traditional criteria after CBT had a predominance of acute GVHD clinical features.
Citation: Bone Marrow Transplantation 48, 1285-1290 (October 2013) | doi:10.1038/bmt.2013.48

Pomalidomide: the new immunomodulatory agent

for the treatment of multiple myeloma
A AChanan-Khan et al.

Abstract
In this report, we provide a comprehensive review on the preclinical and clinical investigations
conducted in development of the next-generation immunomodulatory drug (IMiD) pomalidomide
for the treatment of relapsed/refractory multiple myeloma (MM). We consulted PubMed,
MEDLINE, ASH, ASCO annual symposium abstracts and http://clinicaltrials.gov/ for the purpose
of this literature review. Twenty-six preclinical and 11 clinical studies were examined. These studies
delineate the mechanisms of action of pomalidomide and attest to the robust clinical activity in
relapsed/refractory MM. MM is the second most common hematological malignancy in the US.
Despite availability of several therapeutic agents, MM remains incurable. Thus, the development of
new therapies remains a priority. Pomalidomide is the newest member of the IMiDs class of drugs,
and in preclinical and clinical investigations, it has demonstrated an improved efficacy and toxicity
profile in comparison to its sister compounds, lenalidomide and thalidomide. Importantly, recent
clinical studies have demonstrated its activity in relapsed or refractory myeloma, particularly in
lenalidomide and bortezomib-refractory patients. Thus, the addition of pomalidomide to the antimyeloma armamentarium is widely anticipated to have a significant impact on the overall clinical
outcome of advanced stage relapsed and refractory MM patients.
Citation: Blood Cancer Journal (2013) 3, e143; doi:10.1038/bcj.2013.38

Role of the B-cell receptor and the microenvironment in chronic lymphocytic leukemia
POppezzo and GDighiero

Abstract
Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) remains an
incurable disease. Advances have been made to understand the molecular pathogenesis
underlying CLL progression and treatment resistance. We here review the available evidences
concerning the role of the B-cell receptor (BCR) and the tumor microenvironment interactions
in CLL pathogenesis. Antigen likely has a key role in the selection of the tumoral clone, the
mutational status of immunoglobulin genes is a strong prognostic predictor and BCR signaling
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Alegerea Editorului din Literatur

has been postulated to have a role for CLL trafficking and interaction with the stromal
microenvironment. There is also important evidence, favoring a role for the microenvironment
in CLL pathogenesis. Most, if not all, proliferative events occur in the lymph nodes and bone
marrow, where leukemic cells receive through microenvironment interactions survival signals
aiming to avoid apoptosis and acquire favorable tumoral growing conditions. In addition, the
tumoral microenvironment appears to be the site where the acquisition of additional genetic
lesions in the clone occur, which should greatly influence clinical outcome. The advent of new
tyrosine kinase inhibitors which seem to be able to modulate microenvironment interactions
and circumvent the p53 deletion have generated significant promise by raising the possibility
that they could provide significant progress in disease treatment.

HEMATOLOGY

Citation: Blood Cancer Journal (2013) 3, e149; doi:10.1038/bcj.2013.45

Hematopoietic SCT in Europe: data and trends in 2011

J RPassweg et al.

Abstract
In all, 651 from 680 centers in 48 countries reported 35660 hematopoietic SCT (HSCT) in
32075 patients (13470 allogeneic (42%), 18605 autologous (58%)) to the 2011 survey.
Main indications were: leukemias; 10113 (32%; 94% allogeneic); lymphoid neoplasias;
non-Hodgkins lymphoma, Hodgkins lymphoma, plasma cell disorders; 18433 (57%; 12%
allogeneic); solid tumours; 1573 (5%; 5% allogeneic); and non-malignant disorders; 1830
(6%; 92% allogeneic). There were more unrelated donors than HLA identical sibling donors
(54% versus 39%); proportion of peripheral blood as stem cell source was 99% for autologous
and 73% for allogeneic HSCT. Cord blood was only used in allogeneic transplants (6%
of total). In the past 10 years, the overall number of transplants has increased by 53%.
Allogeneic HSCT have doubled (from 7272 to 14549) while, autologous have increased by
32% and continue to increase by about 1100 HSCT per year since 2001. In the past 2 years,
an increase of >2000 HSCT per year was seen. Transplant activity is shown by team size.
For allogeneic HSCT, we show use of reduced-intensity conditioning versus myeloablative
conditioning across Europe and use of post-transplant donor lymphocyte infusions with
considerable variation across different countries.
Citation: Bone Marrow Transplantation (2013) 48, 11611167; doi:10.1038/bmt.2013.51

Light-chain amyloidosis: SCT, novel agents and beyond

M Rosenzweig et al.

Abstract
Light-chain amyloidosis is a plasma cell dyscrasia characterized by the production of fibrillar
proteins comprised of monoclonal light chains, which deposit in tissues causing multiorgan
dysfunction and death. The diagnosis is challenging and requires a biopsy and often specialized
testing to confirm the subtype of systemic disease. The goal of treatment is eradication of
the monoclonal plasma cell population and suppression of the pathologic light chains, which
improve organ function and extend survival. Standard treatment approaches have included
high-dose melphalan followed by autologous hematopoietic SCT or oral melphalan with
dexamethasone. The use of novel agents (thalidomide, lenalidomide and bortezomib) alone
and in combination with steroids and alkylating agents has shown efficacy and continues to be
explored. A risk-adapted approach to SCT followed by novel agents as consolidation, reduces
treatment-related mortality with promising activity. Immunotherapy targeting pathologic plasma
cells and amyloid fibrils is being developed and could potentially eliminate visceral amyloid
deposits. Improved understanding of the biology that renders light-chains amyloidogenic and
a commitment to refer patients to specialized centers conducting well-designed clinical trials
is essential to improve patient outcomes.
Citation: Bone Marrow Transplantation 48, 1022-1027 (August 2013) | doi:10.1038/bmt.2012.199

44

A novel therapeutic molecule against HTLV-1 infection targeting provirus

A Tanaka et al.

Abstract
Human T-cell leukemia virus type 1 (HTLV-1), which causes adult T-cell leukemia (ATL) in humans, establishes a
life-long latent infection. Current therapies are not very effective against HTLV-1-associated disorders. A novel
therapeutic approach may help to combat HTLV-1 infection. A molecular therapy that targets the proviral
genome is favorable because the therapeutic effect occurs specifically in HTLV-1-infected cells, regardless
of whether they express viral genes. In this proof-of-concept study, we developed a therapeutic molecule
based on zinc finger nuclease (ZFN) to achieve this goal. We designed a ZFN that specifically recognized
conserved region of HTLV-1 long terminal repeat (LTR) and introduced it into various HTLV-1-positive human
T-cell lines, including HTLV-1-transformed and ATL-derived cell lines. The ZFN disrupted the promoter
function of HTLV-1 LTR and specifically killed HTLV-1-infected cells. We also showed a potential approach of
this therapeutic molecule to remove the proviral genome from HTLV-1-infected cells, something that has not
been possible before. The therapeutic effect of ZFN was confirmed in an in vivo model of ATL. This strategy
may form the basis of a therapy that can eradicate HTLV-1 infection. Similar approaches can be used to target
other malignancy-associated viruses.
Citation: Leukemia (15February2013) | doi:10.1038/leu.2013.46

The MLL recombinome of acute leukemias in 2013

CMeyer et al.

Abstract
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk
infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain
reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present
data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia
patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation
partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to
their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia
patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of
121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only
seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene
(~90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and
MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type,
age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the
extending network of reciprocal MLL fusions deriving from complex rearrangements.
Citation: Leukemia (2013) 27, 21652176; doi:10.1038/leu.2013.135;

Reduction of complement factor H binding to CLL cells improves the

induction of rituximab-mediated complement-dependent cytotoxicity
SHrl et al.

Abstract
A main effector mechanism of rituximab (RTX) is the induction of complement-dependent cytotoxicity (CDC).However,
this effector function is limited, because CLL cells are protected from complement-induced damage by regulators
of complement activation (RCAs). A prominent RCA in fluid phase is factor H (fH), which has not been investigated in
this context yet. Here, we show that fH binds to CLL cells and that human recombinant fH-derived short-consensus
repeat 1820 (hSCR1820) interferes with this binding. In complement-based lysis assays, CLL cells from therapynaive patients were differently susceptible to RTX-induced CDC and were defined as CDC responder or CDC nonresponder, respectively. In CDC responders, but notably also in non-responders, hSCR1820 significantly boosted
RTX-induced CDC. Killing of the cells was specific for CD20+ cells, whereas CD20 cells were poorly affected. CDC
resistance was independent of expression of the membrane-anchored RCAs CD55 and CD59, although blocking of
these RCAs further boosted CDC. Thus, inhibition of fH binding by hSCR1820 sensitizes CLL cells to CDC and may
provide a novel strategy for improving RTX-containing immunochemotherapy of CLL patients.
Citation: Leukemia (2013) 27, 22002208; doi:10.1038/leu.2013.169
Martie 2014

45

Instructions for authors

1. Sending the Article
All articles will be accompanied by the signed form of
ownership transfer and by the conflict of interests form
which can be returned by fax or e-mail (as scanned documents). All the responsibility for the originality of the sent
material belongs to the author(s) alone.
The articles can be sent to the following address:
valentin.radoi@mediasyscom.ro
Each article will be evaluated by the peer-review committee composed of two independent peer-reviewers, in a
blinded fashion, according to the peer-review protocol.
Each author must suggest peer-reviewers (preferably
three) for his article. The peer-reviewers must not have the
same affiliations as the authors. Their name, affiliation and
e-mail addresses must be included in the e-mail alongside
the article. The editors reserve the right to use or not use
the peer-reviewers suggested by the authors.
2. Articles sent for publishing
The Romanian Journal of Oncology and Hematology
publishes:
- original articles;
- reviews;
- case reports;
- perspectives;
- consensus declaration coming from an association or
from a group of specialists;
- letters to the editor.
There are no length limits for all articles except for letters
to the editor which can have a maximum of 2500 characters
without spaces. Letters to the editor can be related to an
article already published in the journal or it can represent
original scientific contributions or events news/presentations etc. of interest for the reader.
If, following the peer-review process, the article requires
only minor changes then the manuscript is accepted for
publication in its revised form without further input from
the author. In case the changes are considered more important (scientific errors or an incorrect use of the language
that can affect the quality of the scientific message) the author will be contacted by a member of the editorial committee and it will only be published after he approves the
changes considered necessary by the peer reviewers. In
some cases, based on the written approval of the author(s),
the peer-reviewers and the chief-editor or the publisher the
article may be published alongside the comments of the
reviewer(s).
3. Authors
Each author must be able to prove his active participation in the study by contributing to the concept, protocol,
data gathering or analysis, their interpretation or by critically revising the manuscript. The approval of each author
must be sent alongside the article. Any other persons who
have contributed to the paper, like study participants or colleagues, will be mentioned in the Contribution section.
4. Permissions and Ethics
For citations, tables, figures etc. which are not original,
these must be accompanied by the written permission for
their use and the full reference. Photographs of identifiable
persons must be sent alongside the written permission of
the person(s) and all regions that may allow the identification of the subject must be covered.
The author must have obtained, for all studies including
human subjects, the permission of the subjects to be part

46

of the study whilst keeping their anonymity. By sending the

article, the author declares that he obtained this permission
from all his subjects. All studies must respect the Helsinki
Declaration (1975).
For human and animal studies, the authors must have
obtained the approval of the ethics committee from the
University/Institute/etc. where the study was done.
5. Writing the article
The article must be written in conformity with the general recommendations of the ICMJE (www.icmje.org). The
journal publishes articles written in English or Romanian,
written using the special characters used in each language.
The articles must be sent either as a Microsoft Word 2000
document (*.doc) or as a Microsoft Word 2003 document
(*.docx). The articles will be written using a size 12 for the
characters with one and half (1 1/2) spaces between paragraphs. The manuscript must be sent in its final form. The
pages will be numbered with the manuscript containing
the following sections: Title, Authors, Author Affiliation(s),
complete physical and e-mail address of the corresponding author (on page one of the article), Abstract, Keywords,
the text of article, thanks and/or contributions, Funding
Acknowledgements, Bibliography, the figure(s) and the
table(s) legend. The author(s) assume full responsibility
that the electronic document represents the entire article
as mentioned before and that it is correct at the moment it
was sent, after revisal and after acceptance.
A. The Title of the manuscript will have a maximum of
100 characters without spaces and will represent the main
idea of the article.
B. The author(s) will send their full name(s) and
surname(s), the highest academic position, their full tittles,
their affiliations and the city and country of residence at the
moment the manuscript was written. The corresponding
author will mention his complete physical and e-mail address. Each article can have a maximum of 12 authors with
the exception of the letters to the editor which can have at
most 5 authors and consensus declaration which have no
author limit.
C. Abstracts and Keywords. Each article must have a
bilingual abstract (English and Romanian). The abstracts
can have at most 1000 characters without spaces and will
include:
Introduction - the presentation of the most important
aspects in the studied field as to sustain the hypothesis and
the objective of the study, as well as the reason(s) for which
the study was done;
Methods - the presentation of the main methods used
and the type of study (clinical study, experimental study,
meta-analysis);
Results - the most important results of the study;
Discussion - the significance of the results with an emphasis on the new discovery(ies).
For case presentations we recommend that the authors
first describe the initial condition of the patient, followed by
the clinical and laboratory exams, the discussion of the differential diagnosis and treatment. The case report should
end with the presentation of the evolution of the patient
from admission until the last contact.
For reviews, consensus declarations and perspective articles the abstract will contain a general description of the
article contents. Letters to the editor must not be accompanied by an abstract.
After each abstract the authors must mention 3-5 keywords (in English and Romanian) which will be used for
indexing.

D. Abbreviations. Abbreviations are not accepted in

the title or the abstracts. Measure Units will be expressed
according to the International System. In the text, authors
can use only standard abbreviations (see the AMA manuals for details). All abbreviations must be explained at
their first use in the text.
E. The Article Text
For original articles:
Introduction - a presentation of the most important
aspects in the studied domain without doing a review of
the literature. The purpose of this part is to present and
backup the hypothesis on which the study was based.
Methods - this section will include all required information so that the reader can verify the validity of the
study including, but not limited to, subjects, measurements, statistics and ethics.
Results - the results of the study will be presented in
a descending order of importance. An interpretation of
the results will not be done in this section.
Discussion - the authors will present the way the results backup the original hypothesis, as well as the way
in which the results are backed up or contradicted by the
published literature. A paragraph must be dedicated to
presenting the limitations of the study and another one
must represent a conclusion in which the authors can
present their personal opinion backed up by the study
results and/or the literature.
For all other types of articles we recommend the use of
a clear structure based on sections and sub-sections.
6. Bibliography
The references will be written using the Vancouver
style. The references will be numbered, in the order
they appear in the text as such: (1). All sources found in
the text must be present in the bibliography and all the
papers mentioned in the bibliography must appear in
the text. All journals will be abbreviated according to
international standards. Information obtained from
sources which are not published yet, but are accepted
for publishing will include at the end of the reference
the mention in print between round parentheses. If
the cited results have not been published yet the mention will be personal communication written in the
text of article between round parentheses. Only references read by the authors of the article will be cited.
An original article will have at most 50 references, a
review will have at most 100 references, a letter to the
editor 5 references, whilst all other types of articles will
have the minimum number of references required.
Examples of correct citations:
- For journals: author(s), article title, abbreviated name
of the journal, year, volume, number, first and last page.
Example:
Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul
M. Treatment of human brucellosis: systematic review
and meta-analysis of randomised controlled trials. BMJ.
2008; 336(7646):701-4.
- For articles which arent published in print yet (example):
Evans JD, Gomez DR, Chang JY, Gladish GW, Erasmus
JJ, Rebueno N, Banchs J, Komaki R, Welsh JW. Cardiac
18F-fluorodeoxyglucose uptake on positron emission
tomography after thoracic stereotactic body radiation
therapy. Radiother Oncol. 2013 Sep 6. [Epub ahead of
print] http://dx.doi.org/10.1016/j.radonc.2013.07.021.

- For books: author(s), title, city, publishing house, year.

Example:
Cheers B, Darracott R, Lonne B. Social care practice in
rural communities. Sydney: The Federation Press; 2007.
- For book chapters: chapter author(s), chapter name,
editor(s), book name, edition, city, publishing house,
year. Example:
Rowlands TE, Haine LS. Acute limb ischaemia. In: Donnelly R, London NJM, editors. ABC of arterial and venous
disease. 2nd ed. West Sussex: Blackwell Publishing;
2009.
- For websites: Author(s) (if known). Webpage name
[internet]. Year [date of last change, date of citation]. Exact web address. Example:
Atherton, J. Behavior modification [Internet]. 2010 [updated 2010 Feb 10; cited 2010 Apr 10]. Available from:
http://www.learningandteaching.info /learning/behaviour_mod.htm
The references will be placed in the text in the following way: leading to lymphocytosis (1).
7. Figures, Images, Tables
Figures and Images will be drawn professionally
and sent in separate file(s) as jpeg, tiff or png files at
a quality of a minimum of 300 dpi. In the text, each
figure must be represented by a number, a title and a
description.
The authors will indicate where should the figure
be placed in the text. All images or figures must
come from the authors personal collection or the
author must have rights to publish the image or figure. We do not accept images or figures taken from
the Internet.
Tables will be included in the text and each table will
have a number and a short description if required.
8. Ownership Rights
By sending the article for publication the author(s):
- take full responsibility for the scientific content of the
text and for the accuracy of the send data;
- become (co)author(s) of the manuscript (all further plagiarism accusation are addressed solely to the
author(s) who signed the manuscript);
- declare they are the rightful owners of the images,
figures and/or information sent for publishing and that
they have the permission to publish all the materials for
which they do not own the intellectual property rights;
- declare that the message/content of the manuscript
is not influenced in anyway by commercial interests/
previous engagements/any sort of relations with other
people or companies;
- transfer all rights for the manuscript to Media Systems Communication.
9. Other
Previously mentioned limitations can be ignored in
special cases with the agreement of the chief-editor and/
or the publisher.
All published materials cannot be returned. The editorial office reserves the right to republish the materials in
any journals/magazines.
The official recommendations for medical journals can
be consulted at : www.icmje.org.
Not taking into consideration the recommendations
mentioned before can lead to delay in publishing the
materials or may lead to not publishing the article.
Martie 2014

47

International articles

Instruciuni pentru autori

1. Trimiterea materialelor
Responsabilitatea integral asupra caracterului original
al materialelor trimise spre publicare aparine n ntregime
autorilor.
Materialele vor fi trimise la adresa de mail:
valentin.radoi@mediasyscom.ro
Fiecare articol este evaluat de comitetul de peer-review,
format din doi refereni independeni, respectndu-se anonimatul autorului, conform protocolului de peer-review.
Autorii trebuie s sugereze peer-revieweri (preferabil
trei) pentru articol. Peer-reviewerii trebuie s nu fie afiliai
aceleiai instituii ca i autorii. Numele, afilierea i adresele
lor de e-mail trebuie s fie incluse n e-mail alturi de articol.
Editorii i rezerv dreptul de a folosi sau de a nu folosi peerrevieweri sugerai de autori.
2. Manuscrise publicate/transmise spre publicare
Revista Romanian Journal of Oncology and Hematology
public:
- articole originale;
- rezumate ale literaturii (review-uri);
- prezentri de caz;
- articole de perspectiv;
- declaraii de consens din partea unei asociaii sau grup
de profesioniti;
- scrisori ctre editor.
Nu exista limite de caractere dect pentru scrisorile ctre
editor care vor include maximum 2500 de caractere fr
spaii. Acestea se pot referi fie la un articol deja publicat n
revist, fie pot aduce contribuii originale tiinifice sau legate
de evenimente etc. de interes pentru cititor.
Nu vor fi luate n consideraie articolele publicate anterior n alte reviste. Dac materialul a fost anterior trimis spre
publicare altei reviste i nu a fost acceptat, autorul este invitat
s trimit i comentariile sau rspunsul comitetului de peerreview. n cazul n care, ca urmare a recenziei independente
(peer-review) sau a corecturii stilistice/lingvistice, manuscrisul
necesit modificri minore, articolul este acceptat pentru
publicare n forma revizuit, fr a mai fi solicitat acordul autorului. n cazul n care modificrile sunt considerate majore
(erori tiinifice sau de exprimare care pot afecta calitatea mesajului tiinific transmis), autorul va fi contactat de un membru al colectivului redacional, iar articolul va putea fi publicat numai dup ce autorul aprob efectuarea modificrilor
considerate necesare de peer-revieweri. n anumite cazuri,
pe baza aprobrii scrise att a autorului, ct i a referentului
(peer-reviewer), redactorul-ef i/sau publisher-ul pot decide
publicarea manuscrisului, nsoit de opinia i justificrile re
ferentului.
Ordinea n care sunt publicate n revist manuscrisele
este determinat de data intrrii n redacie, de necesitile
editoriale i de respectarea recomandrilor de mai sus. Pot
surveni prioriti pentru unele articole de actualitate, pentru
materialele solicitate explicit de redacie sau pentru cele care
prezint n opinia redaciei un interes deosebit.
3. Autorii
Fiecare autor trebuie s poat dovedi participarea sa activ
n studiu. Includerea acestora se bazeaz numai pe contribuia
substanial la conceptul, modelul, strngerea datelor sau
analiza, prelucrarea i interpretarea rezultatelor sau revizuirea
critic. Acordul fiecruia pentru versiunea final trebuie trimis o dat cu manuscrisul. Alte persoane care au contribuit
la lucrare, cum sunt participanii la studii, vor fi menionate la
seciunea Contribuii.
4. Permisiuni i etic
Pentru citri, tabele, figuri etc. care nu sunt originale,
acestea trebuie nsoite de permisiunea scris pentru reproducere a autorului mpreun cu referinele n ntregime. Fo-

48

Titlul articolului

tografiile persoanelor identificabile trebuie s fie nsoite de

acordul acestora semnat pentru publicare sau, n caz contrar,
vor trebuie acoperite toate regiunile care permit identificarea
persoanei. Autorul trebuie s fi obinut anterior, pentru toate
studiile care includ subieci umani, permisiunea acestora pentru a face parte din studiu, fiindu-le respectat anonimitatea.
Prin trimiterea articolului autorul declar c a obinut aceast
permisiune de la toi pacienii.
n cazul studiilor cu subieci umani, protocolul trebuie s
respecte Declaraia de la Helsinki (1975).
n cazul studiilor cu oameni sau animale, autorii trebuie s
fi obinut acordul comisiei de etic de la universitatea/institutul/etc. n cadrul cruia studiul a fost realizat.
5. Redactarea articolelor
Redactarea articolelor se conformeaz n general
recomandrilor stabilite de Comitetul Internaional al Editorilor de Reviste Medicale (www.icmje.org). Sunt acceptate
spre publicare manuscrise redactate n limbile englez SAU
romn, redactate n mod obligatoriu folosind diacriticele
romneti pentru manuscrisele n aceast limb. Articolele
se trimit n format Microsoft Word 2000 (extensia *.DOC) sau
Microsoft Word 2003 (extensia *.DOCX), cu corp de liter
de mrimea 12, spaiate la un rnd i jumtate. Manuscrisul
trebuie transmis n forma final, corectat (inclusiv bibliografia) i trebuie s fie coerent din punct de vedere tiinific i
lingvistic. Paginile vor fi numerotate, manuscrisul fiind redactat cu respectarea urmtoarei succesiuni: titlul, autorii, afi
lierea autorilor, adresa complet fizic i de e-mail a autorului
corespondent, rezumatul redactat bilingv (limbile romn
i englez), cuvinte-cheie (limbile romn i englez, ntre
3 i 5), textul propriu-zis al manuscrisului, mulumiri i/sau
contribuii, fonduri obinute pentru realizarea studiului, bi
bliografie, legenda figurilor i a tabelelor. Autorul(ii) i asum
responsabilitatea c documentul electronic este complet i
corect la momentul trimiterii, dup revizuire i acceptare.
A. Titlul manuscrisului va fi concis (maximum 100 de ca
ractere fr spaii) i n concordan cu coninutul lucrrii. Titlul
trebuie redactat att n limba romn, ct i n limba englez.
B. Autori. Autorii vor furniza numele i prenumele complete, gradul universitar, cel mai nalt titlu academic, afilierea,
oraul i ara de reedin la data redactrii manuscrisului. Autorul corespondent i va trece adresa fizic i de e-mail. Fiecare manuscris va fi semnat de maximum 12 autori. Excepie
fac scrisorile ctre editor care pot avea maximum 5 autori
i declaraiile de consens care nu au limit de autori, fiind
obligatorie menionarea numelui grupului.
C. Rezumate i cuvinte-cheie. Fiecare articol trebuie
nsoit de un rezumat redactat obligatoriu n limbile romn
i englez. Fiecare rezumat trebuie s se ncadreze n limita a
1.000 de semne tipografice fr spaii i va cuprinde (n cazul
studiilor originale):
Introducere (Introduction): prezentarea celor mai importante aspecte din domeniul studiat cu scopul susinerii studierii ipotezei i obiectivului studiului, precum i motivul pentru
care a fost ntreprins acest studiu.
Metode (Methods): se vor prezenta principalele metode folosite i tipul de studiu (studiu clinic, experimental,
metaanaliz).
Rezultate (Results): principalele rezultate ale studiului.
Discuie (Discussion): semnificaia rezultatelor; se vor sublinia aspectele noi ale studiului.
Pentru prezentrile de caz se recomand descrierea strii
iniiale a bolnavului, examenului clinic i paraclinic efectuat,
discutarea diagnosticului diferenial i a tratamentului, urmat
de prezentarea evoluiei bolnavului pn la ultimul contact cu
acesta.
Pentru rezumate ale literaturii (review-uri), declaraii de
consens i articole de perspectiv, rezumatele vor cuprinde
descrierea general a tematicii prezentate. Scrisorile ctre
editor nu trebuie nsoite de abstract.

Nume autori

Sub fiecare rezumat vor fi menionate 3-5 cuvinte-cheie (n

limbile romn i englez) care vor fi afiate pentru indexare.
D. Abrevieri. Abrevierile nu sunt acceptate nici n titlu i
nici n rezumate. Unitile de msur vor fi exprimate conform Sistemului Internaional, putndu-se folosi abrevierile
acceptate internaional. n manuscris se vor folosi numai
abrevieri standard, ncetenite n practica medical. n text,
abrevierile vor fi explicate ntre paranteze rotunde la prima
apariie.
E. Text. n cazul articolelor originale n text se va respecta
urmtoarea succesiune:
Introducere - Prezentarea celor mai importante aspecte
din domeniul studiat fr realizarea unui rezumat al literaturii.
Scopul acestei pri a textului este de a prezenta i susine
ipoteza pe care s-a bazat realizarea studiului.
Metode - Aceast seciune va cuprinde toate informaiile
necesare pentru ca cititorul s poat verifica validitatea studiului, incluznd, dar nu limitndu-se la subieci, msurtori,
etic i analiz statistic.
Rezultate - Vor fi prezentate rezultatele studiului, iniial
cele legate de ipoteza principal, n ordinea descresctoare
a importanei. Nu se va realiza o interpretare a rezultatelor n
aceast seciune.
Discuie - Se va prezenta modul n care rezultatele susin
ipoteza iniial a studiului, precum i modul n care rezultatele sunt confirmate sau se afl n contradicie cu rezultatele din literatura publicat. Este obligatorie introducerea unui paragraf care s discute limitrile studiului i a
unei concluzii care s reprezinte opinia autorilor susinut
de rezultatele studiului i/sau a altor articole din literatur.
n cazul celorlalte tipuri de articole publicate de ctre revista Romanian Journal of Oncology and Hematology se
recomand folosirea unei structuri clare bazate pe capitole
i subcapitole.
6. Bibliografie
Pentru referine se va folosi stilul Vancouver. Referinele
bibliografice vor fi numerotate n ordinea n care apar n
text, cu cifre arabe astfel: (1). Este obligatoriu ca toate sursele
cuprinse n bibliografie s fie citate n text; nu trebuie s
apar n text trimiteri la lucrri care nu sunt menionate n
bibliografie. Titlurile periodicelor vor fi abreviate conform
stilului internaional acceptat. Informaiile provenite din surse
nepublicate nc, dar acceptate spre publicare pot fi citate indicaiile respective vor purta ns n bibliografie meniunea
sub tipar ntre paranteze rotunde. Dac lucrarea nu este
acceptat nc, meniunea va fi comunicare personal,
menionat ntre paranteze n text, nu n referine. Nu vor fi
citate dect referine bibliografice care au fost consultate de
autorii articolului. Un articol original nu va include mai mult
de 50 de referine bibliografice. Un review nu va include mai
mult de 100 de referine. O scrisoare ctre editor nu va include mai mult de 5 referine. Celelalte tipuri de articole vor
include numrul minim de referine necesar.
Exemple de citare corect
- Pentru reviste: autorii, titlul original al articolului, revista cu
prescurtrile internaionale, anul, volumul, numrul revistei,
pagina de nceput i de sfrit. Exemplu:
Skalsky K, Yahav D, Bishara J, Pitlik S, Leibovici L, Paul M.
Treatment of human brucellosis: systematic review and
meta-analysis of randomised controlled trials. BMJ. 2008;
336(7646):701-4.
- Pentru articole nepublicate nc n reviste (publicate doar
online):
Evans JD, Gomez DR, Chang JY, Gladish GW, Erasmus JJ,
Rebueno N, Banchs J, Komaki R, Welsh JW. Cardiac 18F-fluorodeoxyglucose uptake on positron emission tomography
after thoracic stereotactic body radiation therapy. Radiother
Oncol. 2013 Sep 6. [Epub ahead of print] http://dx.doi.
org/10.1016/j.radonc.2013.07.021.

- Pentru cri: autorii, titlul original, oraul, editura, anul, numrul paginii. Exemplu:
Cheers B, Darracott R, Lonne B. Social care practice in rural
communities. Sydney: The Federation Press; 2007.
- Capitol de tratat: autorii capitolului, numele capitolului,
editorii, numele tratatului, ediia, oraul, editura, anul publicrii. Exemplu:
Rowlands TE, Haine LS. Acute limb ischaemia. In: Donnelly
R, London NJM, editors. ABC of arterial and venous disease.
2nd ed. West Sussex: Blackwell Publishing; 2009.
- Pentru un site web: Autor (dac este cunoscut). Denumirea paginii web [internet]. Anul publicrii [data ultimei schimbri a paginii, data citrii]. Adresa web exact. Exemplu:
Atherton, J. Behavior modification [Internet]. 2010 [updated 2010 Feb 10; cited 2010 Apr 10]. Available from: http://
www.learningandteaching.info /learning/behaviour_mod.
htm.
n text citrile se vor introduce nainte de punct sub forma (1).
Exemplu: conducnd la limfocitoza observat n periferie (1).
7. Figuri, imagini, tabele
Figurile (desene, scheme) vor fi reprezentate grafic profe
sional i vor fi trimise separat (i nu incluse n cadrul documentului). n document se citeaz numai figurile, consecutiv,
cu cifre arabe, cu un titlu i o legend. Imaginile i figurile
trebuie s fie trimise n format jpg, png sau tiff la minimum
300 dpi. Toate figurile vor fi numerotate cu cifre arabe. Autorii vor indica n text unde trebuie plasate ilustraiile. Se va
preciza sursa imaginii (colecia proprie etc.). Toate imaginile
vor trebui nsoite de o declaraie conform creia autorul manuscrisului este titularul drepturilor de autor pentru imaginea
respectiv i este de acord cu publicarea acestora. Nu se accept fotografii luate de pe internet.
Tabelele vor fi incluse n document i n mod obligatoriu
fiecare tabel va fi numerotat i nsoit de o scurt explicaie i
(dac este cazul) de legend.
8. Drepturi de autor
Prin transmiterea ctre redacie a manuscriselor spre publicare, autorii:
- i asum rspunderea integral pentru coninutul tiinific
al manuscrisului transmis i acurateea datelor prezentate;
- i asum calitatea de (co)autor al manuscrisului (orice
eventual acuzaie ulterioar de plagiat adresndu-se exclusiv autorului/autorilor care au semnat manuscrisul respectiv);
- declar c sunt proprietarii de drept ai imaginilor i/sau
informaiilor propuse spre publicare sau c au permisiunea
de reproducere n vederea publicrii n revista Romanian
Journal of Oncology and Hematology pentru materialele
ale cror drepturi de proprietate intelectual nu le aparin;
- declar pe propria rspundere c mesajul/coninutul
manuscrisului nu este influenat i/sau dictat de interese comerciale, de angajamente prealabile sau de orice alte relaii
cu tere persoane care ar putea fi considerate conflicte de
interese;
- transfer integral drepturile de autor ctre Media Systems
Communication.
9. Alte precizri
Limitrile expuse anterior pot fi ignorate n situaii deosebite, cu acceptul prealabil al Editorului-ef i/sau al Publisherului.
Materialele publicate nu se restituie. Redacia i asum
dreptul de a republica materialele n aceeai revist i/sau de
a aviza favorabil republicarea manuscriselor n alte reviste.
Versiunea oficial i integral a recomandrilor pentru revistele biomedicale se poate consulta la adresa: www.ICMJE.
org. Nerespectarea recomandrilor de mai sus poate duce
la ntrzieri n publicarea materialelor sau la decizia de nepu
blicare a acestora.
Martie 2014

49

o f

j o u r n a l

o f

Doresc s m abonez la O n c o l o g y & H e m at o l o g y

90 RON
160 RON

R o m a n i a n

q Abonament pentru 1 an 4 numere ale revistei

q Abonament pentru 2 ani 8 numere ale revistei

j o u r n a l

R o m a n i a n

JURNAL DEDICAT REZIDENILOR,

REZIDENILOR

, SPECIALITILOR

I
CERCETTORILOR DIN DOMENIUL ONCOLOGIEI,
ONCOLOGIEI HEMATOLOGIEI,
HEMATOLOGIEI MEDICINEI PALIATIVE I TERAPIEI
TERA
DURERII

Oncology & Hematology

TALON DE ABONAMENT

www.romjoh.com

REVIST PUBLICAT SUB EGIDA

N r . 1 / V o l . II / 2 0 1 4
www.medsysc.com

ROLUL COMISIEI DE TUMOR BOARD

N CHIRURGIA ONCOLOGIC

detalii n pagina 16

Nume:................................................................................... Prenume: ...............................................................................

Dna  Dl  Dra 
Adres domiciliu: .....................................................................................................................................................................
Municipiu: ........................................................................ Sect.: ................ Jude:............................................................
Ora:................................................................. Comun: ......................................................................................................
Cod potal: ............................................... Telefon: ...............................................................................................................
Specialitate ................................................................................................................................................................................
 student rezident medic specialist medic primar
Competen ............................................................................... Denumire instituie: .......................................................
Domeniu de activitate:  Privat  Public
Secie: ................................................................................................. Funcie: ......................................................................
Specialitate: ................................................................. Adres instituie: ............................................................................
.................................................... Municipiu: ....................................................Sect.: ........... Jude:.................................
Ora:................................................................. Comun: ......................................................................................................
Cod potal: ............................................... Telefon: .......................................... Mobil: ......................................................
E-mail: ........................................................................ Web: ...................................................................................................
CUI instituie:
da
nu
Pltitor de TVA:
Factur - v rugm s completai cu coordonatele necesare emiterii facturii:
Denumire persoan: ...................................................... Denumire instituie: ..................................................................
Adresa pentru primirea revistelor Media Systems Communication:
Domiciliu
Instituie
Data:

Semntur:..........

Dup completare, v rugm s trimitei talonul nsoit de dovada efecturii plii la adresa:
Media Systems Communication S.R.L.,
Calea Rahovei nr. 266-268, corp 2, etaj 2, camerele 22-23, Sector 5, Bucureti, cod potal 050912,
prin fax (031) 432.82.30 sau scanate prin e-mail la office@mediasyscom.ro. Mulumim!

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se elibereaz n maximum
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sau prin ordin de plat pe coordonatele:
Media Systems Communication S.R.L.,
Calea Rahovei nr. 266-268, corp 2, etaj 2,
camerele 22-23, Sector 5, Bucureti, cod potal 050912,
CUI RO31922876, J40/8111/2013.
Cont RON IBAN: RO05BACX0000000912742000,
deschis la Unicredit iriac Bank, Sucursala Rahova.

Doresc s primesc o copie

a facturii abonamentului:
q Da, la adresa de e-mail:
.....................................................................
q Da, la fax:
.....................................................................

SC MEDIA SYSTEMS COMMUNICATION cu sediul n Bucureti, Calea Rahovei nr. 266-268, corp 2, etaj 2, camerele 22-23, CUI RO31922876, J40/8111/2013
prelucreaz datele cu caracter personal furnizate de dumneavoastr prin acest document n scopul actualizrii bazei de date.
Pe viitor, datele menionate ne permit s v inem la curent cu activitatea noastr.
n cazul n care nu dorii aceast informare, bifai

NU

Conform Legii nr. 677/2001, beneficiai de dreptul de acces, de intervenie asupra datelor, dreptul de a nu fi supus unei decizii individuale.
Avei dreptul s v opunei prelucrrii datelor personale care v privesc i s solicitai tergerea datelor. Pentru exercitarea acestor drepturi,
v putei adresa cu o cerere scris, datat i semnat la sediul social din Calea Rahovei nr. 266-268 corp 2 etaj 2 camerele 22-23, Bucureti.
De asemenea, v este recunoscut dreptul de a v adresa justiiei. Media Systems Communication este nregistrat la
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Nume autori

Martie 2014

51