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Issue 2 I Volume 2 I June 2014
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Romanian Journal of Oncology & Hematology,

recunoscut i pe plan internaional
Aceast primvar a fost cu adevrat una bogat pentru Romanian Journal of
Oncology and Hematology!
Este posibil ca acum s citii aceast revist la ntrunirea Medical Internaional
Translaional i Interdisciplinar HPV - de la biologie molecular la clinic. Poate ai
primit revista direct la spital sau acas, n calitate de membru al Societii Naionale
de Oncologie Medical din Romnia sau al Societii Romne de Hematologie. Este
posibil s fi citit i numrul trecut la Congresul Bienal de Cancer Mamar sau la
Conferina Abordarea Multidisciplinar n Cancer n 2014 din luna mai.
De asemenea, revista este acum indexat n BDI (baze de date internaionale) nc
de la primul numr, baze de date precum: Google Scholar (Google C.), EBSCO
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n Pubmed/Medline, punndu-v la dispoziie, att n print, ct i online, n mod
gratuit, la adresa www.romjoh.com, articole pe teme variate precum:
- tratamentul state of the art n cancerul de vezic urinar (Deeply invasive
(T2-T4) bladder cancer: optimal treatment in 2014 i Novel treatment for muscle
invasive bladder carcinoma);
- tumori ovariene (The endocrine phenotype in ovarian tumors);
- rezistena la citostatice n cancerul mamar (Molecular mechanisms implicated
in citostatic resistance in cancer cells from metastatic breast cancer);
- complicaiile terapiilor biologice n psoriazis (Risk of non melanoma skin cancer
in psoriasis patients with biologic therapy (up to date)).
A dori s mulumesc pentru acest succes al Jurnalului colaboratorilor i editorilor
i s invit toi cititorii la o colaborare ct mai ampl i deschis pentru a aduce cu
adevrat Jurnalul la standarde internaionale.
Valentin Rdoi
Editor-in-Chief Romanian Journal of Oncology and Hematology
University of Medicine and Pharmacy Carol Davila
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
Issue 2 I Volume 2 I June 2014
PUBLISHED UNDER THE AUSPICES OF
THE NATIONAL SOCIETY FOR MEDICAL ONCOLOGY IN ROMANIA; THE ROMANIAN HEMATOLOGICAL SOCIETY; THE ROMANIAN CANCER SOCIETY
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Senior Editors
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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)
Section Editor
Prevention & Screening

Asist. Univ. Mircea O. D. Lupusoru (University of Medicine and Pharmacy Carol Davila;
Director Medical - Spitalul de Psihiatrie Titan Dr. C-tin Gorgos)
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. Adriana Coli (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 Lucrri Dr. Cristian Silviu Voinea (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef Lucrri Dr. Diana Paun (Universitatea of Medicin i Farmacie Carol Davila, Bucureti, Romnia)
Asist. Univ. Gabriela Elena Lupusoru (University of Medicine and Pharmacy Carol Davila)
Asist. Univ. Dr. Carsote Mara (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. Adina Alexandru (Universitate de Medicina si Farmacie "Carol Davila", Bucuresti, Romania)
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. 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 Mallorca Spain)
Dr. David Gmez Almaguer (Universidad Autnoma de Nuevo Len, Monterrey, Mxico)
Dr. Sankalp Yadav (General Duty Medical Officer-II, Chest Clinic Moti Nagar, North Delhi Municipal Corporation, New Delhi, India)
60
Editorial
NOVEL TREATMENT FOR MUSCLE

INVASIVE BLADDER CARCINOMA [en]
Sankalp Yadav
64
76
Calendar
Scientific Events [en]
Review
DEEPLY INVASIVE (T2-T4)

BLADDER CANCER: OPTIMAL
TREATMENT IN 2014 [en]
Raghavan Derek
84
THE ENDOCRINE
PHENOTYPE IN OVARIAN
TUMORS [en]
Mara Carsote, Valentin Radoi, Catalina Poiana
90
MOLECULAR MECHANISMS
IMPLICATED IN CITOSTATIC
RESISTANCE IN CANCER CELLS
FROM METASTATIC BREAST
CANCER [ro]
Daniela Zob, Dana Lucia Stanculeanu,
Iuliana Gruia
98
RISK OF NON MELANOMA

SKIN CANCER IN PSORIASIS
PATIENTS WITH BIOLOGIC
THERAPY (UP TO DATE) [ro]
Ana Livia Duta, Cristina Medeleanu,
Cristiana Voicu, Madalina Maftei,
Victor Gabriel Clatici
104
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Editorial
Novel treatment for muscle invasive bladder carcinoma
Novel treatment for muscle

invasive bladder carcinoma
Sankalp Yadav*
Chest Clinic Moti Nagar
Corresponding author: Dr. Sankalp Yadav MMBS, PGDEM
Chest Clinic Moti Nagar, New Delhi, PIN-110015
Tel.: +918 447 11 25 32
E-mail: drsankalpyadav@gmail.com
Open Access Article
Keywords:
Cystectomy, muscle-invasive bladder cancer, radiotherapy, neoadjuvant chemotherapy
Bladder cancer is a global health problem with
the worldwide age standardized incidence rate
(ASR) for bladder cancer being 10.1 per 100,000
for males and 2.5 per 100,000 for females.(1,2)
It accounts for 4.1% of male and 1.8% of female
deaths per year from cancer and is the second
most common urinary tract cancer.(3) In males, after
prostate, lung and colorectal cancer, it is the fourth
most commonly diagnosed cancer.(4) Bladder
cancer is common in geriatric age groups with
the median age of diagnosis being 73 years. 70%
of patients aged 65 or older are diagnosed with
bladder carcinoma, and out of these, nearly one
half of diagnoses occur in patients older than 75
years.(5) Urothelial cell carcinoma formerly known
as transitional cell carcinoma (TCC) accounts for
more than 90% of all the bladder cancers out of
which 70% are non-muscle invasive bladder cancer
(NMIBC) at diagnosis.(6-9) However, the NMIBC
can also progress to muscle invasive bladder
cancer (MIBC).(2) Also, the chance of developing
invasive bladder cancer increases with age.(10)
The deeply invasive bladder carcinoma (T2-T4) is
a cancer with a 50% cure rate.(11) In recent years,
rapid and continuing advances in our knowledge
and the use of newer techniques and treatments
have transformed our understanding for finding
a suitable cure for this global health problem,
but still the best treatment modality has not been
definitively established. In this editorial, I discuss
the treatment options available for muscle invasive
bladder cancer.
Treatment options in muscle invasive

bladder cancer
Cite this article:
Yadav S. Novel treatment
for muscle invasive
bladder carcinoma. Rom
J Oncol Hematol. 2014;
2(2):60-62.
60
Several therapeutic options are available to

patients with muscle-invasive bladder cancer
(MIBC). Presently, the available treatments involve
radical cystectomy with or without concurrent
chemoradiation followed by perioperative
chemotherapy. The treatment options are also

dependent on the extent of the disease i.e.
whether the cancer is localized or metastasized. A
number of studies involving the use of neoadjuvant
chemotherapy are underway to find the best
treatment for invasive bladder cancer but the
progress is relatively slow.
In localized invasive bladder cancer, radical
cystectomy with lymphadenectomy has been the
gold standard of treatment and has been used
extensively in the USA. The cure rate is determined
by a number of factors.(11) Radical cystectomy can
be used in both young and old patients, but the
study by Gray PJ et al. (2013) suggested that,
in older patients, this technique has not been
extensively used.(16) Although the data obtained
from various studies reveals that cystectomy is
generally safe and effective in highly selected
older patients (17,18), the relapse rate for T3-4 MIBC
is at least 50%, with most relapses occurring at
distant sites, suggesting the presence of occult
micro-metastases at initial presentation.(11) Radical
cystectomy has its limitation like the physical and
emotional impact it has on the patient.
As a result of the mental and physical side effects
of radical cystectomy, patients are inclining towards
bladder preservation transurethral surgeries but
the level of local control of the tumor is very limited
with this approach.(11,19) The use of these surgeries
is mainly dependent on the size, site of the lesion
and absence of deep infiltrating tumors, but even
in these conditions, only partial cystectomy is
possible.(11,20)
Alternatively, radiotherapy is also used in those
who are not willing to undergo radical cystectomy
and the results are impressive in those studies
that used a higher dosage especially those
cumulatively greater than 60-65 Gy.(21-27) However,
these studies had some limitations as the patients
treated were characteristically older and less
Sankalp Yadav
robust than those subjected to cystectomy.(11)

In patients with more extended tumors (greater
than or equal to T3b) and those older than 75
years of age radiation therapy alone cannot cure
the disease. In such cases palliative treatment
modalities should be considered, particularly if
cisplatin-based chemotherapy is not practically
possible.(28)
So far, whether radical cystectomy is superior to
radiotherapy or vice versa is not proven. Radical
cystectomy may give better results if performed
by an expert due to more local control of the
cancer.
The combination therapy involving the use
of systemic chemotherapy with radiotherapy or
surgery has been studied extensively in view of
sparing the bladder or to improve overall survival
(11)
However, there is the risk of delaying primary
therapy and creating side effects without benefit as
30-60% of bladder cancers show some resistance
to chemotherapy.(11)
Classical adjuvant chemotherapy delivered after
radical cystectomy has been studied but the results
suggest a disease free state .(29-33) However, disease
free survival cannot be considered as an indicator
of success in the presence of salvage therapies.(11)
Current clinical guidelines strongly recommend
to consider the use of neoadjuvant cisplatinbased chemotherapy prior to cystectomy in cases
of muscle-invasive bladder cancer (MIBC).(34,35)
These guidelines are predicated on randomized,
phase III trials showing a survival benefit with this
treatment modality. (36,37) Cisplatin chemotherapy
is common in present neoadjuvant chemotherapy
regimens for MIBC. Although cisplatin has been
used for the systemic management of bladder
cancer for decades it has nephrotoxic effects.
(38,39)
As a result of this, there is a certain cutoff for
renal function in clinical trials evaluating cisplatinbased regimens. A common threshold in current
day clinical trials is a creatinine clearance (CrCl)
of 60 mL/min, below which patients are deemed
ineligible.(40) However, these renal thresholds
vary, with different groups utilizing thresholds
of 45 and 55 mL/min.(41-43) The efficacy of
neoadjuvant therapy may be based on either
cytoreduction of the primary tumor, resulting
in a more complete and successful surgery, or
elimination of micrometastatic disease burden.
Advanced pathologic tumor stage and presence
of metastasis are associated with a higher risk of
death from bladder cancer. But the use of adjuvant
chemotherapy is associated with improved
survival, supporting the need for prospective
clinical trials to assess the role of multimodal
therapy in these patients.(44) Neoadjuvant cisplatinbased chemotherapy is the standard of care for
muscle-invasive bladder cancer (MIBC); however,
it is less frequently adopted in practice because
of concerns regarding nephrotoxicity and delay of

cystectomy.(45) Waehre H et al. (1993) suggested
that the survival rates improved with the use of
chemotherapy in patients with deeply infiltrating
(greater than or equal to T3) bladder cancer but
appeared to represent an overtreatment in patients
with T2 tumors.(46)
The largest prospective study of squamous
cell carcinoma and transitional cell carcinoma
using neoadjuvant combination chemotherapy
with gemcitabine/cisplatin conducted by Khaled
HM et al. (2014) suggested that neoadjuvant
combination chemotherapy with gemcitabine/
cisplatin did not improve survival rates in locally
advanced bladder cancer over radical cystectomy
alone.(47) However, they also suggested that
bladder preservation was feasible, and the
results in overall survival rates, in responding
patients, were positive. Therefore, predictive
models to select patients are needed.(47)
The recent studies published involving the
balloon-occluded arterial infusion (BOAI) of cisplatin/
gemcitabine, with concomitant hemodialysis and
irradiation (the so-called OMC [Osaka Medical
College] regimen) for bladder preservation in
patients with muscle-invasive bladder cancer and
lymph node metastasis have shown good results.
The OMC regimen has shown no adverse systemic
effects, and it delivers an extremely high concentration
of anticancer agent at the site of the tumor, as well
as the pelvic area. Even in patients aged 85 years
no severe toxicities were noted and therapy was
completed successfully. Thus, the OMC regimen
can be considered as a new option for patients with
MIBC.(48)
Besides, there are a number of other challenges
that plague deeply invasive bladder carcinoma care.
Tomaszewski et al. suggested that patients who had
care transition were more prone to treatment delay
of 3 months, thus advocating the need to improve
care transitions for better quality of care.(49) Also the
skill of the surgeon and centers where the patient
undergoes treatment determine the outcome.
Conclusion
There are multiple treatment options for MIBC and
most are governed by the stage of the cancer, extent
of the disease spread and patient related factors.
However, radical cystectomy has been utilized as the
gold standard in the past and even in the present
day for local disease in the USA. Although various
modalities like radiotherapy, chemotherapy, etc. are
available, the best treatment for the particular patient
is largely based on multiple factors. In the future, the
treatment will be mostly determined by molecular
prognostication and prediction studies. Surgery and
radiation usage are definitive for local disease but
the use of chemotherapy requires further advanced
clinical studies. The newer treatment modalities like
June 2014
61
Editorial
neoadjuvant chemotherapy are promising but are
not extensively studied and thus a bigger number
of multi-centric clinical studies will help in finding
the best treatment with greater chances of survival
Novel treatment for muscle invasive bladder carcinoma
in patients suffering from deeply invasive bladder

cancer.
Conflict of Interests: None.
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patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy.
Lancet Oncol. 2011; 12:211214.
41. Siefker-Radtke AO, Dinney CP, Shen Y, Williams DL, Kamat AM et al. A phase 2 clinical trial
of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine
followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: Final
results. Cancer. 2012; 119(3):540-7.
42. Bellmunt J, Guillem V, Paz-Ares L, Gonzalez-Larriba JL, Carles J et al. Phase I-II study of
paclitaxel,cisplatin,and gemcitabine in advanced transitional-cell carcinoma of the urothelium.
Spanish Oncology Genitourinary Group. J Clin Oncol. 2000; 18:32473255.
43. Pal SK, Ruel N, Villegas S et al. CKD-EPI and Cockcroft-Gault Equations Identify Similar
Candidates for Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer. PLoS One.
2014; 9(4):e94471.
44. Clifton MM1, Psutka SP, Boorjian SA et al. Cancer-specific mortality following radical
cystectomy for bladder cancer with lymph node involvement: impact of pathologic disease
features and adjuvant chemotherapy. World J Urol. 2014 May 15. [Epub ahead of print]
doi:10.1007/s00345-014-1319-0
45. Plimack ER, Hoffman-Censits JH, Viterbo R et al. Accelerated Methotrexate, Vinblastine,
Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for MuscleInvasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates
of Response and Toxicity. J Clin Oncol. 2014 May 12. [Epub ahead of print] doi:10.1200/
JCO.2013.53.2465
46. Waehre H, Ous S, Klevmark B et al. A bladder cancer multi-institutional experience with
total cystectomy for muscle-invasive bladder cancer. Cancer. 1993; 72(10):3044-51.
47. Khaled HM, Shafik HE, Zabhloul MS et al. Gemcitabine and Cisplatin as Neoadjuvant
Chemotherapy for Invasive Transitional and Squamous Cell Carcinoma of the Bladder: Effect
on Survival and Bladder Preservation. Clin Genitourin Cancer. 2014 May 6. [Epub ahead of
print] pii:S1558-7673(14)00080-9 doi:10.1016/j.clgc.2014.04.002
48. Azuma H, Inamoto T, Takahara K et al. The novel bladder preservation therapy BOAI-CDDPradiation (OMC-regimen): a new treatment option for invasive bladder cancer patients with
lymph node metastasis. Int J Oncol. 2014; 44(6):1895-903.
49. Tomaszewski JJ, Handorf E, Corcoran AT et al. Care transitions between hospitals are
associated with treatment delay for patients with muscle invasive bladder cancer. J Urol. 2014
May 14. [Epub ahead of print] pii:S0022-5347(14)03556-3 doi:10.1016/j.juro.2014.05.027
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obtain permission from the license holder to reproduce the material. To view a copy
of this license, visit http://creativecommons.org/licenses/by-nc/4.0/
Yadav Sankalp
Events
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Scientific Events
ONCOLOGY
64
European Congress
of Oncology Pharmacy 2014
8th European Scientific

Oncology Conference
26 - 28 June 2014
02 - 04 July 2014
Krakow, Poland
On behalf of the European Society of Oncology
Pharmacy (ESOP) and the Organising Committee,
we warmly welcome you to the second European
Conference of Oncology Pharmacy (ECOP), in the
time-honoured city of Krakow, Poland, 26-28th
June 2014.
Close co-operation between oncology physicians and
oncology pharmacists is essential for optimal patient
care. ECOP 2014 offers a tremendous opportunity for
exchange and debate between its 2,500 members,
colleagues and partners worldwide.
The primary focus of this unique European
Conference is to promote the highest standards
of pharmaceutical care in the management and
support of patients with tumours. The latest
advances in research, patient management and
practice are being showcased in keynote lectures,
scientific symposia and poster sessions in two
distinct tracks, clinical and practical.
We know that a multi-professional, multidisciplinary
approach in oncology will not only ensure
economic use of resources but also significantly
improve patient safety.
We would like to take this opportunity to invite
you to the Opening Event held in the exhibition
area of the Conference venue, providing you the
opportunity to meet colleagues from around the
world, to network in a convivial setting and forge
new links for future collaboration.
Lastly, but by no means least, our host city will
match the exciting promise of the Conference itself.
Speakers, participants, guests and friends should
make time to discover the wonderful city that is
Krakow with its wealth of historical buildings.
We trust that you will return from the Conference
inspired by colleagues from around the world and
that you will have made new friends and scientific
contacts that will support you in your essential work.
We are delighted to be welcoming you at what
promises to be a highly educational, collaborative
and successful conference.
Yours,
Klaus Meier
President of ESOP
Marbella, Mlaga, Spain,
It is our pleasure to invite you to the 8th European

Scientific Oncology Conference (ESOC-8) to be held
in Marbella (Mlaga, Spain) on 2nd- 4th July 2014. As
in previous years, the ESOC meeting will highlight the
best and latest findings in all areas of cancer research.
The Conference will be devoted to new promising
anticancer agents in the latest pre-clinical stages
or already in Phase I or II clinical studies.
The most relevant clinical investigators working on
new drug development will actively participate in a
very comprehensive Scientific Program, with Keynote
Lectures from experts and specific Symposia devoted
to the presentation and discussion of individual data
from different clinical research groups.
Investigators attending the Conference will benefit
from hearing about all these advances and will
have the opportunity to exchange their opinion
with the experts in very lively discussions.
All this in the exceptional surroundings of one of
the most attractive places in the South of Spain,
We look forward to seeing you in Marbella!
B. Chabner | Chairmen | H. Corts-Funes
12th Annual Meeting

of Japanese Society of Medical Oncology
17 - 19 July 2014
Fukuoka City, Japan
Dear Colleagues:
We warmly welcome you to attend the 12th Annual
Meeting of JSMO, which will be held in Fukuoka
from July 17 to 19 (Thursday to Saturday) 2014 in

Fukuoka City, Japan. The theme of the meeting is
Comprehensive Cancer Therapy - From Translational
Research and Chemotherapy to Cancer Survivorship.
Though advances in research on cancer biology
and translational research have resulted in many
molecularly targeted agents and new treatment
modalities, Japan and other Asian countries must
deal with a rapid increase in cancer patients and
survivors, especially among the elderly. The 12th
Annual Meeting will discuss not only advances in
cancer-targeted therapies, but also geriatric oncology
and the management of cancer survivors. We expect
to continue our collaboration with oncology societies
from the US and EU, as well those from Asian-Pacific
regions. Please join us in the international sessions to
discuss issues that are vital to oncology.
Fukuoka is a wonderful city to spend time in. It
is located on Kyushu Island in the southwestern
part of Japan, approximately 1000 kilometers
southwest of Tokyo. Fukuoka is a 90-minute
flight from Tokyo, just over an hour from Seoul,
2 hours from Taipei and 4.5 hours from Beijing.
Because of its central location, Fukuoka has been
Japans gateway to other Asian countries over the
millennia, and has many interesting sites that are
influenced by the Asian continent. There are also
many fine restaurants within and around Fukuoka,
where you can enjoy Hakata (Fukuoka) cuisine and
fresh locally-sourced seafood, meats, vegetables
and fruits at reasonable prices. We are certain that
you will enjoy stimulating discussions and have
many memorable experiences in Fukuoka during
your stay. The members of the secretariat of the
12th JSMO 2014 Annual Meeting look forward to
welcoming you to Fukuoka in July of next year.
Kazuo Tamura, M.D., Ph.D.
Congress President, 12th Annual Meeting of JSMO
Professor of Internal Medicine, Fukuoka University
Pan Pacific Lymphoma Conference

21-25 July 2014
Kohala Coast, Hawaii, USA
The University of Nebraska Medical Center, Center
for Continuing Education invites you to participate
in the 2014 Pan Pacific Lymphoma Conference on
July 21-25, 2014 at the
The Fairmont Orchid, The Kohala Coast, Hawaii.
Trusted for almost two decades for its educational
excellence, this international conference brings
together more than 400 members of the
multidisciplinary lymphoma clinical team including
oncologists, hematologists, pathologists, clinical
scientists, nurse practitioners, physician assistants,
nurses,and pharmacists.Afull complement of research
and clinical case presentations, symposiums, posters,
and exhibits make this conference one of the largest
gatherings of clinicians and researchers specializing
in the area of lymphoma and transplantation.
The 2014 conference will include scientific sessions

Monday through Friday, and two-hour symposiums
throughout the conference.
OBJECTIVES
At the conclusion of the conference, the attendees
should be better able to:
1. Apply recent trial results with current and
emerging agents and regimens to develop
evidence-based clinical management strategies
for Non-Hodgkin lymphoma (NHL) and Hodgkin
lymphoma (HL).
2. Develop an algorithm for the optimal
management of patients with lymphoma, inclusive
of multi-modality therapies and maintenancebased regimens, across the disease continuum.
3. Personalize lymphoma treatment regimens based
upon patient- and disease-specific characteristics.
4. Evaluate the optimal patient selection, timing,
and regimen for stem cell transplant in patients with
lymphoma.
5. Identify criteria related to the appropriate timing
and patient selection for ongoing clinical trials
using novel therapies.
SCOS Annual Membership Conference

Diagnosis to Palliation: The Complete
Spectrum of Cancer Care
01 - 02 August 2014
Charleston, SC, USA
Welcome to the South Carolina Oncology Society
(SCOS)! Our mission is to provide advocacy for
cancer patients and to promote standards of
excellence for high-quality cancer care.
SCOS is committed to adding clarity to both the
clinical and business aspects of oncology care,
offering our members access to meaningful,
current, and helpful information and education.
6th Latin American

Conference on Lung Cancer
21 23 August 2014
Lima, Peru.
Welcome Message
Dear Colleagues,
On behalf of the International Association for
the Study of Lung Cancer (IASLC) and the Local
June 2014
65
Events
Scientific Events
Organizing Committee, it is a great pleasure and

an honor to extend to you a warm invitation to
attend the 6th Latin American Conference on Lung
Cancer (LALCA 2014) to be held August 21 23,
2014 in Lima, Peru.
Lung Cancer is still the leading cause of death not
only in Latin America but worldwide. Building on
the success of the previous conferences in Chile,
Argentina and Brazil, international and national
speakers will discuss the science and advances in
the treatment and prevention of lung cancer and
thoracic malignancies worldwide and Latin America
in particular.
Simultaneous translation English >< Spanish will
be provided for all sessions.
With tobacco being the leading cause of morbidity
and mortality worldwide and its consumption
leading to respiratory and cardiovascular disease,
as well as cancer, the Conference would like to
support the Framework Convention for Tobacco
Control and will again host a Tobacco Forum on
Thursday, August 21.
We encourage physicians, nurses, other clinicians,
researchers and scientists in the lung cancer field
and those interested in any aspect of thoracic
oncology to attend this conference. It is only
through an exchange of the widest variety of
research that we can offer the best program and
benefits to our members and patients.
We expect more than 500 delegates from Latin
America to attend this unique event and we
encourage everyone to submit an abstract before
the abstract submission deadline June 13, 2014.
We hope you will join us in Lima, the beautiful
capital of the Republic of Peru, where you can enjoy
its historical center with beautiful colonial churches
and mansions; as well as its modern site with its
suburbs offering a spectacular view of the Pacific
Ocean. Or you might want to take a couple of extra
days and enjoy an amazing journey to the center
of the world Cusco with its beautiful surroundings
and Inca ruins, followed by a leisurely train ride to
the enigmatic citadel of Machu Picchu one of the
most amazing urban creations of the Inca Empire at
2,430m above sea-level, in the middle of a tropical
mountain forest.
We look forward to welcoming you to an inspiring
educational program in Lima, Peru in August
2014.
Carlos Vallejos Sologuren
Luis E. Raez
LALCA 2014 Conference Chair
4th International Thoracic Oncology

Congress Dresden
Advances through Molecular Biology
in Thoracic Cancer
12 - 14 September 2014
Dresden, Germany
66
Welcome!
We are pleased to invite you to the 4rd International
Thoracic Oncology Congress Dresden in midSeptember, 2014 titled: Advances through
Molecular Biology in Thoracic Cancer.
Our lung cancer congress will be a great
opportunity for lung cancer professionals working,
both, in the laboratory and in clinic, in the field of
basic and translational research and in daily patient
care, to share the most updated knowledge and
views concerning the development of innovative
therapies.
More than 50 of the most experienced lung cancer
specialists including epidemiologists, molecular
biologists, pathologists, pulmonologists, radiologists,
surgeons, radiotherapists and medical oncologists
will participate in the scientific program and their
contributions will provide participants with new
information on current patient care and research.
In addition to the outstanding scientific program
being offered, we at the same time would like to
encourage participants and guests to enjoy the
great cultural opportunities of Saxony and the
fabulous baroque city of Dresden.
We look forward to seeing you in Dresden on
September 12th - 14th, 2014.
Nico van Zandwijk
Giorgio V. Scagliotti
Christian Manegold
NCCN 9th Annual Congress:

Hematologic Malignancies
19 20 September 2014
New York, New York, USA
Treatment of hematologic malignancies is
increasingly complex. Issues relating to pathology,
transplantation, and various new therapies require
oncologists and hematologists to stay abreast
of breakthrough advances. In addition, targeted
therapies and oral treatments bring the latest
benefits to patients. This Congress focuses on the
new approaches that have been incorporated into
patient management, including the use of drugs,
biologics, and diagnostics.
The NCCN 8th Annual Congress: Hematologic
Malignancies took place September 20 21,
2013 in New York, NY. Accredited materials from
this congress are available through the NCCN
Continuing Education Portal.
ESMO 2014 Congress

Madrid, Spain
The theme for ESMO 2014 is Precision Medicine

in Cancer Care. Whether you are a medical or
surgical oncologist, radiotherapist, immunologist
or pathologist, practicing precision medicine
means we are all working towards a common
goalimproved patient outcomes. This is the
ultimate goal of ESMO 2014.
Attendees can expect detailed exploration of the
practical, political, and financial issues that stand
between our ideals and the reality of implementing
optimal care for every person suffering from
cancer.
Invitation from the Congress President
It gives me great pleasure to invite you to ESMO
2014 in Madrid 26- 30 September 2014.
I am particularly looking forward to this Congress,
because it continues the powerful momentum
established at our ESMO 2012 meeting in Vienna,
which broke so many records for European
oncology conferences: 16,394 delegates,
140 scientific and educational sessions, and a
remarkable 30% rise in the number of abstract
submissions 1,238, of which 31 were latebreaking. ESMO 2012 set the standard for what
a congress should be: deep, comprehensive,
and up-to-the-minute. ESMO 2014 will raise that
standard to a new level.
As the leading network for medical oncologists in
Europe, ESMO takes very seriously its responsibility
to inform, educate, and support each individual
practitioner and researcher in our fast-evolving
discipline.
in Cancer Care, an ideal that has rapidly shifted
from in some distant future to just around the
corner. We are looking forward to presentations
of some of the most recent research and
trials including targeted therapies and
immunotherapeutic approaches, joint symposia
with representatives of all cancer specialities,
and robust debates on the clinical challenges
of supplying genuinely personalised cancer
treatment across Europe. We are also, naturally,
looking forward to yet another record-breaking
crop of abstracts!
ESMO is committed above all to supporting
each medical oncologist with the best and
most up-to-date information and educational
materials. ESMOs Clinical Practice Guidelines,
OncologyPRO online educational and scientific
resources, and our scientific journal Annals of
Oncology give practitioners across Europe and

around the world access to the scientific and
medical knowledge that supports best practice.
A congress is most of all about interaction, and
ESMO 2014 will offer both the clear and efficient
organization that attendees have come to expect
from ESMO as well as plentiful opportunities to
make new contacts, discuss new findings, learn
from experts, and review presentations both at
the Congress itself and online.
All this will take place in Madrid in late summer:
one of Europes most beautiful and vibrant cities,
with a proud medical tradition and a wealth of
cultural and gastronomic delights only minutes
away from the Congress venue.
Patients are waiting for delivery on the promise of
precision medicine. We oncologists still have much
to do to further improve cancer care. I look forward
to seeing you in Madrid and helping to accelerate
our profession into its next phase.
Welcome from the Committee Chairs
It is now increasingly clear that cancer is a very
personal disease that requires an individualized
treatment approach. How can we possibly identify
and effectively treat this massive collection of
diseases each sub-type with its own individual
molecular makeup? For a long time, this seemed
an insurmountable challenge to optimal cancer
care: although the disease was clearly individual
and heterogeneous, treatment was necessarily
based largely on statistical collective analyses
and results a best fit for a population, but not
necessarily for each individual sufferer.
Today, thanks to advances in molecular biology and
genomics, this no longer has to be the case. As we
gain greater insights into carcinogenesis, we are
at the point where genuinely targeted therapy is
now possible for an increasing number of cancers.
We are also rapidly moving from a site of origin
based disease classification to a genomics-based
taxonomy of these complex and diverse diseases,
with revolutionary implications for clinical practice,
for research, and for teaching. ESMO is at the
forefront of this rapidly changing landscape, a vital
point of reference for the oncology profession. This
is why you cannot afford to miss the 2014 ESMO
Madrid Congress.
in Cancer Care. Providing optimal treatment for
patients according to individual circumstances
and the molecular characteristics of their disease is
also a key theme for ESMO when developing new
conferences, products and services. Whether you
are a medical or surgical oncologist, radiotherapist,
immunologist or pathologist, practicing precision
medicine means we are all working towards a
common goalimproved patient outcomes. This is
the ultimate goal of ESMO 2014.
ESMO 2014 will offer the chance to share that
knowledge in a dynamic, peer-to-peer environment,
where new ideas and new collaborations appear
spontaneously at every corner. Nothing is better
than face-to-face contact amongst professionals.
June 2014
67
Events
Scientific Events
In Madrid, ESMO will provide a Scientific and

Educational Programme that builds on the highly
successful models of ESMO 2010 in Milan and
ESMO 2012 in Vienna, while extending breadth
and depth. You can expect to learn about the latest
results in basic, translational, and clinical research,
expressing the broader concepts of precision
or personalised medicine in specific treatment
options.
The personalised paradigm for care demands
more than ever a multidisciplinary approach: you
can expect practical seminars and wide-ranging
debates about how specialities can work together
to achieve ever-greater precision in cancer care.
Delivering precision medicine is not just a scientific
challenge: you can expect detailed exploration
of the practical, political, and financial issues
that stand between our ideals and the reality

of implementing optimal care for every person
suffering from cancer. From the academic lab to
the busy clinic, the scientific programme at ESMO
2014 aims to connect all the dots for you.
This also depends, in part, on you: the research
abstracts and trials reports that you provide will
help ensure that the Scientific and Education
Programme is truly a conversation among
peers. Your contribution will help to inspire
the collaborative discussions that advance our
profession and gain you the recognition that your
work deserves.
We look forward to meeting you in Madrid and to
exchanging expertise. This is a remarkable time
for cancer care a time when we can all make a
difference. We invite you to seize the opportunity.
HEMATOLOGY
68
2014 PAN PACIFIC LYMPHOMA

CONFERENCE
7th Africa Society For Blood Transfusion

(afsbt) Biennial International Congress
21 - 25 July 2014
30 July - 2 August 2014
Hawaii, USA
Welcome message:
At the conclusion of the conference, the attendees
should be better able to:
1. Apply recent trial results with current and emerging
agents and regimens to develop evidence-based
clinical management strategies for Non-Hodgkin
lymphoma (NHL) and Hodgkin lymphoma (HL)
2. Develop an algorithm for the optimal
management of patients with lymphoma, inclusive
of multi-modality therapies and maintenancebased regimens, across the disease continuum
3. Personalize lymphoma treatment regimens based
upon patient- and disease-specific characteristics
4. Evaluate the optimal patient selection, timing,
and regimen for stem cell transplant in patients
with lymphoma
5. Identify criteria related to the appropriate timing
and patient selection for ongoing clinical trials for
novel therapies
Event Committee Roster:
James O. Armitage, MD
Joe Shapiro Professor of Medicine
Division of Oncology and Hematology
Department of Internal Medicine
University of Nebraska Medical Center
Julie M. Vose, MD, MBA
Neumann M. and Mildred E. Harris Professor
Chief, Division of Oncology and Hematology
Department of Internal Medicine
University of Nebraska Medical Center
Welcome message:
The AfSBT will host its 7th AfSBT International
Congress in 2014. Zimbabwe is hosting the event
and the venue of the congress is Victoria Falls. The
congress is organised by AfSBT through the Local
Organising Committee (LOC). One of the key
committees of the LOC is the Scientific Committee
(SC). The Scientific Committee is composed of
the International Scientific Committee (ISC) and
the Local Scientific Committee (LSC). National
Blood Service Zimbabwe (NBSZ) is partnering
Zimbabwe Medical Association (ZiMA) and
Zimbabwe Quality Assurance Programme
(ZINQAP) in organising this congress. ZiMA and
ZINQAP are also represented in the LOC and
LSC.
Victoria Falls, Zimbabwe
26th World Congress Of The

International Union Of Angiology
10 - 14 August 2014
Sydney, Australia
Welcome message:
The XXVIth World Congress of the International
Union of Angiology (IUA) will take place at the
Hilton Hotel, Sydney, Australia from Sunday 10th
to Thursday 14th August 2014.
The IUA is a Society for Vascular Biology,
Medicine, Surgery and Phlebology, with
the red, blue and yellow rings of the IUA
logo signifying the full spectrum of arterial,
venous and lymphatic disorders which will
be presented at the Sydney meeting. The
Congress will be held in conjunction with the
Australasian College of Phlebology 2014 Annual
Scientific Meeting, and in association with
the International Society for Vascular Surgery,
the Australasian Society of Thrombosis and
Haemostasis, the Australian and New Zealand
Society of Phlebology, the Australian Wound
Management Association, with participation of
the Royal Society of Medicine Vascular Medicine
Section, the Cochrane Peripheral Vascular
Diseases Group, the French Society of Vascular
Medicine, the Italian Society for Angiology and
Vascular Medicine, the International Surgical
Thrombosis Forum and other vascular societies
and institutions affiliated with the IUA.
The program will feature multidisciplinary
symposia, key-note lectures, free paper
sessions, consensus meetings and workshops
on a wide range of topics, including arterial
and venous thrombosis, anti-thrombotic
and anti-platelet drugs, aortic and arterial
aneurysms, cardiovascular and cerebrovascular
disease, atherosclerotic risk factors and
screening, prevention and management of
acute stroke, hypertension, peripheral arterial
disease, critical limb ischaemia, diabetes
and
related
complications,endovascular
treatment of arterial and venous disease,
vascular malformations, lymphoedema, wound
management, evidence based medicine,
vascular imaging, prevention and management
of venous thromboembolism and chronic
venous disease.
This will be the first time that the biennial
IUA world congress has come to this region.
Vascular physicians, angiologists, cardiologists,
haematologists,
vascular
surgeons,
phlebologists,
interventional
radiologists,
vascular sonographers, scientists, wound care

specialists and vascular nurses are invited to
visit Australia in August 2014 where Sydney
will provide an ideal venue for a unique and
productive multidisciplinary scientific exchange
for delegates from around the world to the
XXVIth World Congress of the International
Union of Angiology.
Professor John Fletcher,
IUA President-Elect
Iseh 2014: 43rd Annual

Meeting Of The International
Society For Experimental
Haematology
21 - 24 August 2014
Montreal, Canada
Welcome message:
Make your plans now to attend the annual forum
for the exchange and discussion of original,
unpublished and significant research advances
in the areas of hematology and stem cell biology.
This exclusive scientific meeting, 21-24 August
2014, willfeature leaders in the field as well as
promising young scientists.
Unique with its intimate format, the ISEH 43rd
Annual Scientific Meeting features more than 30
educational sessions, featuring lectures by our
distinguished panel.
The New Investigators track provides those
entering the field the opportunity to meet and
connect with highly regarded ISEH scientists.
Speakers:
Ben Ebert, Harvard Stem Cell Institute & Brigham
and Womens Hospital, Boston.
Sean Morrison, UT Southwestern Medical Center,
Texas.
Scott Armstrong, Memorial Sloan Kettering
Cancer Center, New York.
David Traver, UC San Diego.
George Daley, Harvard Stem Cell Institute and
Boston Childrens Hospital.
Guy Sauvageau, Universit de Montral.
Connie Eaves, Terry Fox Laboratory, Vancouver.
Recipient of the 2014 ISEH Metcalf Award
Toshio Suda, Keio University, Japan.
Recipient of the 2014 ISEH Till and McCulloch
Award
Emmanuelle Passegue, UC San Francisco.
New Investigator Lecturer at the 2014 ISEH Young
Investigator Session
Simon Mendez-Ferrer, CNIC, Madrid
June 2014
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Scientific Events
26th European Congress Of Pathology

30 August - 3 September 2014
London, UK
Welcome message:
Dear Colleague,
The 26th European Congress of Pathology (ECP
2014) will for the first time be organised as a
joint venture between the European Society of
Pathology and the Pathology London 2014 Ltd (a
trading subsidiary of The Pathological Society of
Great Britain and Ireland).
It will be held, from 30 August to 3 September
2014 in the ExCeL Centre in London, United
Kingdom.
On behalf of the European Society of Pathology
and the Pathological Society of Great Britain and
Ireland we would like to invite you to join us in
London for a meeting that will be both exciting
and involving, reflecting the rapid changes
in our profession, both in unravelling disease
mechanisms and in our clinical diagnostic
working practice.
The motto of the Congress Understanding
Disease is the well-known mission statement
of Pathological Society of Great Britain and
Ireland. And it is timely, now that we have greater
understanding of many diseases arising from
the ongoing revolution in genetics and other
translational research methods.
Pathology is more than ever at the centre
of clinical decision making, resulting in new
challenges and opportunities. It is the philosophy
of both the European Society of Pathology and
the Pathological Society of Great Britain and
Ireland that through better understanding of
diseases we can improve the quality of diagnosis
and treatment of patients.
The London 2014 scientific programme aims to
bring science, translational research and clinical
application together to provide delegates
with a comprehensive forum for dissemination
of research findings, exploration of modern
technologies and up to date education.
In addition to providing a rewarding scientific
and educational programme the London 2014
meeting will bring together pathologists and
scientists from all over the world in a convivial
environment providing a memorable social
experience.
We are looking forward to welcoming you and
spending a great time in London.
Han van Krieken
President of the European Society of Pathology
Ian Ellis
President of the Pathological Society of Great
Britain and Ireland
70

An Ellis, UK
Richard Byers, UK
Adrienne Flanagan, UK
Nicholas Rooney, UK
Han van Krieken, The Netherlands
Fred T. Bosman, Switzerland
Fatima Carneiro, Portugal
Michael Wells, UK
3rd World Congress

On Controversies
In Hematology
Istanbul, Turkey
Welcome message:
Dear Friends and Colleagues,
We are delighted to invite you to participate
in the 3rd World Congress on Controversies in
Hematology (COHEM) which will take place in
Istanbul, Turkey on September 11-13, 2014.
Following the success of the 1st and 2nd
COHEM Congresses, which attracted almost
1,000 participants collectively from more than 60
countries, the 3rd COHEM Congress will continue
the unique and successful debate format of the
previous Congresses.
The 3rd COHEM Congress will share up-to-date
information and provide a unique opportunity
for world class leaders in the field to debate
vital and contentious issues in Hematology.
This thought-provoking academic dialogue will
address the most challenging current clinical
and technological questions.
By allocating substantial time for discussions
following each debate, audience members are
encouraged to take a pro-active role in this
academic dialogue. These stimulating debates
will provide clinicians with state-of-the-art
recommendations regarding patient care.
We invite you to attend the 3rd COHEM Congress
in Istanbul and to take an active role in this
innovative and interactive experience.
We look forward to welcoming you at this rewarding
scientific event!
Prof. Robin Fo
Prof. Rdiger Hehlmann
Prof. Emili Montserrat
Prof. Eliezer Rachmilewitz
Prof. Giuseppe Saglio
Prof. Charles Schiffer
Co-Chairpersons
The 19th International Symposium

On Endoscopic Ultrasonography
Chennai, India
Welcome message:
Welcome to Chennai!
It is our great pleasure to invite you on behalf
of the organizing committee and outstanding
faculty to attend the 19th International Symposium
on Endoscopic Ultrasonography to be held in
Chennai, India, from September 18-20, 2014.
EUS was once considered a niche technology
meant for a selected few. Not anymore. With
continual improvements in the technology, what
was purely a diagnostic and staging procedure
has evolved to include tissue acquisition and
of late, interventions. Increased opportunities
for training and the availability of educational
resources have enabled an increasing number of
endoscopists to acquire the requisite technical
skills. These developments have facilitated the
penetration of Endoscopic Ultrasound centers
that were once limited to large tertiary referral
institutions to smaller institutions in secondary
cities and even outpatient clinics. With these
changes, the technology that was once confined
to Japan and to the West has made its way to
the East with an increasing number of new
centers being commissioned every year. This
symposium, although deeply rooted in tradition,
is evolving with the rapidly changing landscape
of EUS. The biannual symposium that used to
rotate between United States, Europe and Japan
has recently been held in emerging nations such
as China and Russia. In 2014 it will be in Chennai,
India! Chennai is a cosmopolitan southern
coastal city that is home to several multinational
corporations, software and manufacturing
industries. With numerous multispecialty and
teaching hospitals, Chennai is a very popular
destination for medical tourism and is referred
to as the Mecca of Medicine in India. The city
is also home to the second longest shoreline,
numerous temples of historical interest and an
unparalleled cuisine.
EUS 2014 will have two components: A two-day
program that will include live demonstrations
of basic and advanced EUS procedures
combined with state-of-the art lectures and
a half day program specially designed for
beginners that will include practical tutorials by
experts. Live demonstrations will include radial
examinations, fine needle aspiration techniques
interpreted in real-time by cytopathologists as
well as interventional procedures. The future

environment within gastrointestinal endoscopy
dictates that we not only be efficient in our
practice but also remain as self-sufficient as
possible. Therefore, a major focus of this
symposium will be on EUS-related cytopathology
to enable endosonographers to independently
assess for diagnostic adequacy. We believe that
this step is very important to further improve our
patient outcomes.
To meet our goals and to provide a world-class
experience we have assembled the best faculty
from around the World who will enthusiastically
share their knowledge, wisdom and experience. We
believe that this symposium will provide you with
invaluable information that will have an immediate
and significant impact on your endosonography
practice. We sincerely hope that you will join us in
Chennai for EUS 2014!
Yours sincerely,
Chairperson
Shyam Varadarajulu
USA / India
Nageshwar Reddy
India
Secretary General
K.R. Palaniswamy
India

Program Committee
Takao Itoi
Japan
Michael Levy
USA
Bertrand Napoleon
France

Advisory Committee
Paul Fockens
The Netherlands
Robert Hawes
USA
Zhendong Jin
China
Thomas Rsch
Germany
Kenjiro Yasuda
Japan

Invited Faculty
Amol Bapaye
India
Vikram Bhatia
India
Kenneth Binmoeller
USA
Kenneth Chang
USA
Pierre Deprez
Belgium
Vinay Dhir
India
Pramod Garg
India
Angels Gines
Spain
Lawrence Ho
Singapore
Atsushi Irisawa
Japan
Nirag Jhala
USA
Mouen Khashab
USA
Masayuki Kitano
Japan
Sandeep Lakhtakia
India
Alberto Larghi
Italy
Laurent Palazzo
France
Ian Penman
UK
Mathew Philip
India
Rajesh Puri
India
Vipulroy Rathod
India
Michael Wallace
USA
Aiming Yang
China
June 2014
71
Events
Scientific Events
International Cytokine
Society Conference
Melbourne, Australia
Welcome message:
The 2014 meeting of the International Cytokine
and Interferon Society is to be held in Melbourne,
Australia, during October 26-29, at the state-of-theart Melbourne Convention Centre. The meeting
will provide an outstanding forum for basic science
and clinical researchers to present their latest data
and exchange ideas relating to the broad role of
cytokines and interferons in human disease, and
applications to therapies.
The topics will include aspects of the biology,
signal transduction and gene regulation
related to cytokines, interferons and their
receptors in innate and adaptive immunity,
pattern recognition receptors and their role
in
host-pathogen
interactions,
infectious
diseases, inflammation, cancer, autoimmunity
and metabolism. Sessions will include cutting
edge basic science and clinical presentations
in plenary and concurrent symposia, as well as
eminent keynote presentations, and are strongly
supported by poster sessions.
In addition to academic basic scientists and clinical
investigators, the meeting will provide strong
networking opportunities for scientists in the
biotechnology and pharmaceutical industries. The
broad attendance and blend of senior scientists
and physicians, as well as graduate students and
post-doctoral fellows will help assure a vibrant and
exciting conference for all.
If you would like to be updated about this
conference, please add your name to the mailing
list by clicking the button on the right.
o Shizuo Akira (Osaka University, Japan)
o K Mark Ansel (University of California San
Francisco, USA)
o Frances Balkwill (Barts Cancer Institute, UK)
o Gabrielle Belz (Walter and Eliza Hall Institute,
Australia)
o Jeff Babon (Walter and Eliza Hall Institute,
Australia)
o Andrew Brooks (University of Queensland,
Australia)
o Yinon Ben-Neriah (Hebrew University-Hadassah
Medical Centre, Israel)
72
o Zhijian James Chen (University of Texas

Southwestern Medical Center, USA)
o Daniel Cua (Merck Research Laboratories, USA)
o Vojo Deretic (University of New Mexico, USA)
o Mark Febbraio (Baker Institute, Australia)
o Richard Flavell (Yale University School of
Medicine, USA)
o Frederic Geissman (Kings College, UK)
o Florent Ginhoux (Agency for Science, Technology
and Research, Singapore)
o Elizabeth Hartland (University of Melbourne,
Australia)
o Veit Hornung (University of Bonn, Germany)
o Kate Jaffrey (Harvard Medical School, USA)
o Zhengfan Jiang (Peking University, China)
o Simon Jones (Cardiff University, UK)
o Thirumula-Devi Kanneganti (St Jude Childrens
Research Hospital, USA)
o Eicke Latz (University of Bonn, Germany)
o Fabienne MacKay (Monash University, Australia)
o Kingston Mills (Trinity College, Ireland)
o Denise Monack (Stanford University, USA)
o Masaaki Murakami (Osaka University, Japan)
o Gabriel Nunez (University of Michigan, USA)
o Keiko Ozato (National Institutes of Health (USA)
o Belinda Parker (La Trobe University, Australia)
o Stefan Rose-John (University of Kiel, Germany)
o Chuck Samuel (University of California Santa
Barbara, USA)
o Feng Shao, (National Institute of Biological
Sciences, China)
o Mark Smyth (Queensland Institute of Medical
Research, Australia)
o Dale Umetsu (Genentech, USA)
o Uwe Vinkemeier (University of Nottingham, UK)
o Carola Vinuesa (Australia National University,
Australia)
o Xiao-Fan Wang (Duke University, USA)
o Wolfgang Weninger (Centenary Institute,
Australia)
o Hua Yu (Beckman Research Institute, USA)
o Elina I Zuniga (University of California San Diego,
USA)
38th European Congress

Of Cytology 2014
Geneva, Switzerland
Topics:
Gynecologic cytology
Lung
Thyroid
Liver & Pancreas
Genitourinary
Soft tissue & bone
Infectious diseases
Veterinary
Lymph node
Hematopathology
Pediatric
Salivary gland
Head & Neck incl. ophthalmic

Central nervous system/ CSF
Breast
Fluids
Automation & quality assurance
Others
2nd International Conference

On Hematology & Blood Disorders
29 September - 1 October 2014
Baltimore, USA
With the burgeoning response received for The

International Conference on Hematology & Blood
Disorders from the Editorial board, Organizing
Committee members and the attendees, OMICS
Group follows the same heel of success. We are
overwhelmed to announce the launch of our
2nd International Conference on Hematology
& Blood Disorders. The remarkable event is
to be held during September 29- October 01,
2014 at Baltimore, USA. We welcomeall the
hematologists, immunologists, pathologists,
oncologists, industrial professionals from
biomedical and healthcare sectors, research
scholars, students and all interested to be a part
of our eventful event.
Hematology-2014 will witness a conglomeration of
various arenas of Hematology under a single roof of
knowledge. The scientific sessions of Hematology2014 has been designed on vivacious topics like
Lymphocytosis, Stem cell research, Anticoagulants,
Bone marrow transplants, Immunoglobulins and
other plasma proteins. The meeting is sure to
generate cerebrating discussions and stream out
multidirectional flow of knowledge along with
fostering beneficial collaborations.
With the well-organized scientific program
hosting sessions on Hodgkins lymphoma,
Thalassemia, treatments for plasma &platelet
disorders, inherited blood disorders etc, along
with topics like host defense and disorders,
drug discovery in hematology, consultative
hematology, thrombosis and Hemostasis and
more, Hematology-2014 is expected to offer
a better and firm platform for the researchers,
students, business delegates and all attendees.
This international event is an effort to discover
a weapon to fight against chronic diseases like
blood cancer ,sickle cell anemia, hemophilia,

Lymphoid malignancies and myeloma, promising
a better future for the progeny and a better
tomorrow for the springing research.
Hematology-2014 is sure to make you ponder,
raise your insights, conflate present and future
and cogitate on ideas and reality. Mark your
schedule, come, connect andconfer aboutyour
researchat this International scientific meeting,let
novel discoveries and research advancements
flourish. Your rejoinder is our inspiration, right
information is our aspiration. Hope to see you at
Hematology-2014.
Welcome message:
Acknowledged as the leading open access
publication model,OMICS Publishing Group
is recognized by its authentic and consistent
contributions to the scientific community.
OMICS Grouphosts over 300 leading-edge
peer reviewed Open Access journals and has
organized over 100 scientific conferences
all over the world.OMICS Group believes
that, The Right to Information should be
Universaland with the aim of accelerating
scientific discoveries, commencing from the
year 2008, OMICS Group has been involved
in providing a momentous platform for
the world renowned scientists, researchers
andtalented
student
community
from
academicinstitutions to participate in the best
academic conferencesin the globe along with
the collaboration initiatives with the leading
entrepreneurs from industries.
OMICS Group journals possess over 3 million
readers and the fame and success of the
same can be attributed to the strong editorial
board which contains over 30000 eminent
personalities ensuring the rapid, quality and
quick review processing.
With
the
burgeoning
response
ofthe
International Conference on Hematology
& Blood Disorders-2013from the Editorial
board, Organizingcommittee members and the
conference delegates,OMICS Groupwould like
to carry forward the same heel of success and
overwhelmed to announce the launchof its2nd
International Conference on Hematology &
Blood Disorders.
This astoundingevent is going to be held
during September 29- October 01, 2014 at
Baltimore, USA.OMICS Group International
conferences always striveto unite people
withdiverse expertise under a single roof
of knowledge. On behalf of the organizing
committee,OMICS Group welcomes all the
hematologists, immunologists, pathologists,
oncologists, research scholars, industrial
professionals and student delegatesfrom
biomedical and healthcare sectorsto be a
part of the esteemed Hematology-2014. The
conference will witness a conglomeration of
various arenas in Hematology, sure to make
you ponder, raise insights, conflate present
June 2014
73
Events
Scientific Events
withfuture and cogitate on ideas and reality.

Mark your schedule, come, connect and confer
about your research atHematology-2014,one
of the exquisitemedical meetings hosted
byOMICS Group.
Hematology-2014is an attempt to explore a
weapon against chronic diseases like blood
cancer,hemophilia,
lymphoma,
myeloma,
leukemia, sickle cell anemia etc., promising
a better future for the progeny and a better
vision for the springing research. Hematology
2014 is anticipated to be one amid the best
scientific conferences in USA.
The scientific sessions of this international
conference on hematology has been designed
on vivacious topics such as Hodgkins lymphoma,
lymphocytosis, stem cell research, anticoagulants,
bone marrow transplants, immunoglobulin and
other plasma proteins.
Hematology-2014 is consisting of well-organized
scientific program and effervescent speeches by
the expertise.OMICS Groupscientific conferences
always
encouragethe
young
researchers
and students to share their excitement and
enthusiasm with world class expertise.
OMICS Groupscientific conference sareastonishing
scientific events for the discussion and collaboration
of the industrial personalities and medical
professionals. Hematology-2014will stream the
multidirectional flow of knowledge fostering
beneficial partnering prospects.Hematology-2014
is going to be held in the charm city, Baltimore;
participating Hematology-2014world congress
would bean excellent opportunity to explore the
beautiful city besides gaining knowledge. Let the
novel discoveries and research advancements
flourish at Hematology-2014, one of the most
remarkable medical conference amidst all the
OMICS Group meetings
Goal/Objective of the Event:
On the Path of Identifying Novel Therapeutics
for Blood Disorders
Hematology-2014 Organization Committee
Enzi Jiang
Research Associate
Department of Hematology and Oncology
University of Southern California, USA
Gouri Adel
Clinical Biochemist/Head
Laboratory of Medical Biochemistry
IBN ZOHR Public Hospital, Algeria
Paul Bajaj
Professor
Department of Orthopaedic Surgery
David Geffen School of Medicine
University of California, Los Angeles, USA
Mark A. Guthridge
Researcher
Australian Centre for Blood Diseases
Monash University, Australia
Michael A. Firer
74
Associate Professor
Department of Chemical Engineering and
Biotechnology
Ariel University Center, Israel
Aldo Iacono
Professor
Department of Pulmonary and Critical Care
Medicine
University of Maryland, USA
Charles S Greenberg
Professor
Department of Medicine and Pathology
Medical University of South Carolina, USA
Gabriela Gheorghe
Director Hematology
Department of Pathology Childrens Hospital of
Wisconsin
USA
Dr Erhabor Osaro
Associate Professor of Haematology and Laboratory
Medicine
School of Medical Laboratory Science
Usmanu Danfodio University
Sokoto, Nigeria
Daniel Tsun-Yee Chiu
Distinguished Professor
Department of Medical Biotechnology and
Laboratory Science
Dean of Research & Development
Chang Gung University
Taiwan, China
Effie Liakopoulou
Executive Director
Partners in Personal Oncology, USA
Helen Philippou
Associate Professor
Division of Cardiovascular and Diabetes Research
University of Leeds, UK
Speakers:
This international event will surely be a stream
of knowledge sharing by many renowned
personalities such as Dr. Daniel Tsun-Yee Chiu, Dr.
Erhabor Osaro, Dr. Michael A. Firer, Dr. Dr. Effie
Liakopoulou, Dr. Enzi Jiang, Dr. Mark A. Guthridge,
Dr. Aldo Iacono, Dr. Charles S Greenberg, and Dr.
Paul Bajaj. Scientific sessions will be chaired by the
expertise from USA, UK, Japan, China, Australia
and Canada.
Conference Highlights
Red Blood Cells
Diagnosis, Treatment and Management of
Blood Disorders
Hematologic Malignancies
Immunology and Hematology
Host Defence and Disorders
Stem Cell Research in Hematology
Blood Transplantation
Thrombosis and Hemostasis
Drug Discovery in Hematology
Consultative Hematology
Research on Various Blood Disorders
Recent Advancements in Hematology
Nume autori
June 2014
75
Review
Deeply Invasive (T2-T4) Bladder Cancer: Optimal Treatment in 2014?
DEEPLY INVASIVE (T2-T4) BLADDER CANCER:

OPTIMAL TREATMENT IN 2014?
Derek Raghavan
President, Levine Cancer Institute
Carolinas HealthCare System
Charlotte, NC, USA
Corresponding author: Derek Raghavan MBBS, MD, PhD, FACP, FRACP, FASCO
Levine Cancer Institute, Carolinas HealthCare System, PO Box 32861, Charlotte, NC, 28232-2861
Tel.: 980 442 3115 Fax: 980 442 3101
E-mail: derek.raghavan@carolinashealthcare.org
Open Access Article
Abstract
Keywords:
Dasatinib, Sprycel, Large
Granular Lymphocytes,
Lymphocytosis,
Acute Lymphoblastic
Leukemia, Philadelphia
Chromosome
Invasive bladder cancer has a cure rate of only 50%, when all T
stages are considered. The pattern of relapse reflects systemic
spread, and metastases occur despite local control. This
suggests that occult metastases are present at presentation. For
more than 30 years, treatment has focused on the use of
systemic chemotherapy before, during or after loco-regional
therapy to control occult systemic disease. More aggressive
surgery and more precise radiation techniques combined with
systemic chemotherapy have also been tested to improve local
control. Gene analysis has been applied extensively to this
clinical problem, with a focus on prediction and prognostication,
but results have not translated into a defined survival benefit.
Although new agents have been tested in the neoadjuvant and
adjuvant setting, no level 1 evidence has been published in the
peer-reviewed literature to show that they offer benefits over the
neoadjuvant approach using the MVAC or CMV regimens.
Biology of Invasive Bladder Cancer

Invasive bladder cancer, representing about
20% of new cases, includes tumors that penetrate
through the lamina propria into muscle and
beyond. Thus about 15,000 new cases occur each
year in the USA, and one must remember that some
cases of non-invasive bladder cancer eventually
Received:
04 March 2014
become invasive, but are not reflected in national
Accepted:
incidence figures. In the USA, a reasonable
04 April 2014
estimate is that more than 20,000 patients require
treatment for invasive, clinically non-metastatic
bladder cancer per year. Most bladder cancers
Cite this article:
Raghavan D. Deeply inva(90%) are urothelial carcinomas (UC), formerly
sive (T2-T4) bladder cancer: termed transitional cell carcinomas (TCC) (1), and
Optimal treatment in 2014.
other cell types include squamous cell carcinoma,
Rom J Oncol Hematol.
adenocarcinoma, small cell carcinoma and very
2014; 2(2):76-82.
76
rarely sarcoma, lymphoma, or melanoma (2,3).

Most invasive bladder tumors are moderately to
poorly differentiated (1). Our xenograft studies
suggested the existence of a stem cell tumor of
origin in bladder cancer, explaining why urothelial
carcinoma may coexist with (and perhaps give rise
to) squamous and glandular patterns of cancer (4).
We have also demonstrated clonal heterogeneity,
reflected in histology and ultrastructure, tumor
growth kinetics, expression of growth factors and
their receptors, and response to treatment (4). Thus
bladder cancer is a complex cancer to treat (5).
When planning treatment of invasive disease, it
is important to consider conventional predictors
of outcome stage and grade are dominant
prognosticators (1,6), and solid growth pattern, large
Derek Raghavan
size, aneuploidy, lympho-vascular invasion and the

presence of hydronephrosis which may also have
an adverse prognostic import (1,6,7). More recently,
the expression of several individual genes and
gene mutations has been shown to correlate with
natural history or response to treatment, including
epidermal growth factor receptor (EGFR), RAS,
P53, RB, P21 and several gene panels (8-17). These
novel prognosticators are increasingly being
factored into potential treatment algorithms for
invasive bladder cancer.
EGFR expression has been shown to correlate
with natural history and extent of invasion (9,10)
and has also been assessed as a predictor of
response to therapy. For example, the Radiation
Therapy Oncology Group (RTOG) have carried
out retrospective analyses of their series of
cases treated with radiotherapy and cisplatinbased chemotherapy, and have demonstrated
that expression of EGFR is associated with
improved outcome, including response to
chemo-radiotherapy, whereas expression of the
HER-2-NEU gene has been shown to correlate
with reduced response and survival after such
treatment (18).
One controversial issue has been the clinical
significance of mutation of the P53 suppressor
gene as a predictor of response to systemic
chemotherapy. There are conflicting data on
whether mutation of P53 confers increased
responsiveness or increased resistance to the
impact of chemotherapy. Cote and colleagues
have reported a post hoc study of immunohistochemical staining of tumor biopsies from a
randomized study of adjuvant platinum-based
chemotherapy (19) and suggested that tumors
exhibiting mutation of P53 benefited from adjuvant
chemotherapy. By contrast, those with wild-type
P53 did not exhibit any benefit from adjuvant
chemotherapy. The major problem with this study
was the small sample size and that it was carried
out on specimens obtained from a trial that was
not specifically designed to answer this question.
Studies from the Memorial Sloan Kettering
Cancer Center initially suggested that P53 mutation
was associated with resistance to neoadjuvant
chemotherapy with the methotrexate-vinblastinedoxorubicin(AdriamycinR)-cisplatin
(MVAC)
regimen (20). A detailed study of molecular
prognosticators in patients treated with the
MVAC or the cisplatin-methotrexate-vinblastine
(CMV) regimens for advanced bladder cancer
at Princess Margaret Hospital, Toronto, did not
identify any prognostic impact from expression
of P53 immunohistochemically (21).
Takata et al (22), reported a small number
of patients treated with a variant of MVAC
chemotherapy and identified another series of
potential genetic predictors of outcome using
array techniques. The significance of their

preliminary observations will require validation,
but it is noted that their data also suggested
that P53 gene function and mutation predict the
outcomes of chemotherapy.
However, we recently published the results of a
randomized trial that tested the efficacy of adjuvant
MVAC chemotherapy in patients with P T1-2,No,Mo
urothelial cancer, using the same laboratory that
had indicated the prior positive correlation (19), but
were unable to confirm the prognostic significance
of P53 mutation, and also did not confirm a survival
benefit from adjuvant MVAC chemotherapy (23).
While there are many potential explanations for
these observations relating to trial methodology
and execution, and the exclusion of P3-4 disease,
the fact is that the study was negative.
Multidrug or pleiotropic resistance, in which
cell surface protein complexes help to export
cytotoxics from cancer cells, thus reducing their
effective concentration and ability to kill the cells,
may be relevant to urothelial malignancy. The
demonstrable presence of multidrug resistance
(MDR) proteins, including p-glycoprotein,
correlates with resistance to several cytotoxics,
including the taxanes, vinca alkaloids and
anthracycline antibiotics. This has been found
in ovarian cancer and multiple myeloma, but
studies of expression of MDR in bladder cancer
have been less definitive, for reasons that are not
well understood. For example, our xenograft
studies identified major clonal differences in
response to doxorubicin and vinblastine, but
we were unable to demonstrate clear and
reproducible expression of p-glycoprotein in the
tumor specimens. Siu et al (21) assessed patients
treated with MVAC or CMV chemotherapy
and did not find any prognostic impact from
p-glycoprotein, although this may have been
influenced by the presence of cisplatin in both
regimens, an agent that is not influenced by
MDR expression, or may have reflected sample
size and other statistical considerations. Petrylak
et al (24) showed increased p-glycoprotein in
pre- and post-treatment biopsies of human
tumors treated with the MVAC regimen. The
highest proportion of tumor cells expressing
p-glycoprotein was observed in metastases
from patients treated with six or more cycles
of chemotherapy. They suggested that MDR
could contribute significantly to the patterns of
resistance seen in the use of the MVAC regimen,
although it is not clear that this translates directly
to invasive, non-metastatic bladder cancer.
Definitive Local Treatment

Radical surgery for invasive bladder cancer:
The standard of care for most patients with
invasive bladder cancer is radical cystectomy with
Martie
June 2014
77
Review
lymph node dissection (25-27). The cure rate depends

on well-defined prognostic factors, including
conventional indices, such as stage and grade,
and the more recent correlates discussed above.
In addition, it appears that delay in cystectomy
may lead to impaired survival (27), and it has been
suggested that the experience of the surgeon is
also critically important to optimal outcomes.
Cure is even possible from surgery alone in locally
advanced stage disease, although the chance
is much lower (25, 26). In experienced centers, the
relapse rate for T3-4 disease is at least 50%, with
most relapses occurring at distant sites, suggesting
the presence of occult micro-metastases at initial
presentation.
Preservation of the Bladder
Some patients are not sufficiently robust to
undergo radical surgery, or choose to avoid this
approach because of the physical and emotional
impact.
Extensive transurethral resection is
occasionally used as the first surgical approach
to deeply invasive bladder cancer, although the
level of local control is usually inadequate (28). In
carefully selected cases, with a solitary lesion on
the dome of the bladder, one that is distant from
the bladder neck and ureters, with at least a 2cm
margin of surrounding normal bladder tissue, and
absence of carcinoma-in-situ, partial cystectomy
may be possible (28,29). This allows preservation of
the intact bladder, albeit sometimes with a smaller
capacity. When used in isolation, surgical bladder
preserving techniques are associated with a higher
local relapse rate.
The use of radiotherapy as an alternative to
radical surgery was generally favored in parts of
Europe and Canada in the past, even for medically
healthy patients. When interpreting published
outcome data, it should be noted that patients
treated in radiation series are characteristically
older and less robust than those subjected
to cystectomy. The traditional approaches to
radiotherapy included doses of external beam
irradiation in the range of 50-70Gy, with a higher
level of local control achieved in series reporting
higher dose schedules, and especially those
cumulatively greater than 60-65 Gy (30-36).
Whether the newer techniques of intensity
modulated radiation therapy (IMRT) and image
guided radiotherapy will truly improve local
control and/or reduce local tissue toxicity remains
to be seen (30). Although the bladder moves
(physiologically) to some extent, despite the fixity
of bony landmarks, with appropriate treatment
planning, the movement of the bladder does not
appear to affect treatment outcomes (34). Various
approaches have been studied in an attempt to
improve local control, to shorten the duration of
treatment or to ameliorate toxicity, but without a
major impact to date (35).
78
After many decades of comparison, there is

still no absolute proof regarding the superiority
of radical cystectomy over radical radiotherapy,
although my own experience is that surgery
yields more reliable local control if performed
by an expert. This view remains controversial
and has not been proven in randomized trials.
In my clinical practice, for medically fit patients
without major additional medical disorders, I
usually refer patients with deeply invasive disease
for radical cystectomy, reasoning that useful
information is gained from surgical staging, and
that local control is likely to be more certain. As
discussed below, in 2014, when radiation is to be
employed, the best local control, and probably
survival, are achieved by a combined chemoradiation approach, as discussed below.
Combination Of Therapeutic Modalities

The combination of systemic chemotherapy
with radiotherapy or surgery has been studied
extensively in the past few years in the hope of
sparing the bladder or to improve overall survival
(7)
. This is based on the concept that systemic
chemotherapy may reduce the extent of local
tumor while controlling micro-metastases, that
prospective evaluation of tumor response is
enabled (especially with neoadjuvant therapy),
and that chemotherapy and radiation may
synergize the anti-cancer effect locally. There
is, however, the risk of delaying primary therapy
and creating side effects without benefit as 3060% of bladder cancers show some resistance to
chemotherapy.
Of importance, the Canadian group showed,
in a randomized, prospective trial, that single
agent cisplatin administered during the period
of radiotherapy resulted in 67% sustained pelvic
tumor control compared to 45% from radiation
alone (37). However, overall survival was not
statistically different, despite a survival trend in
favor of the combined modality therapy, but this
study was not powered to demonstrate a survival
benefit.
In a series dominated by clinical stage T2 bladder
cancer, James et al have reported a randomized
comparison
of
radiotherapy/5-fluorouracilmitomycin versus radiotherapy alone, and showed
improved response rate, progression-free and
overall survival from the combination arm (38).
Neo-Adjuvant Chemotherapy
The role of neoadjuvant (first-line) systemic
chemotherapy, followed by definitive radiotherapy
or cystectomy has been studied in detail (7). The
early, randomized trials, employing single agent
chemotherapy, did not show any survival benefit
compared to local treatment alone. The introduction
of cisplatin-based multi-drug regimens, such as MVAC
and CMV, led to modest but statistically significant
Derek Raghavan
REGIMEN
MEDIAN SURVIVAL
(months)
ACTUARIAL LONG-TERM SURVIVAL

(years)
PUBLISHED
Shipley (53)
CMVC-RT v C-RT
36 v 36
48% 5yr v 49% 5 yr
1998
Griffiths (40)
CMV RT/S v RT/S
44 v 37.5
35% 10 yr v 30% 10 yr
2011
Grossman (41)
MVACS v S
77 v 46
42% 10 yr v 35% 10 yr
2003
Skinner
S v S CAP
30 v 52
39% 5 yr v 44% 5 yr
1991
Stockle/Lehman
S v S MVEC**
~24 v ~34
19% 10 yr v 26% 10 yr
2006
Freiha
S CMV v S
63 v 36
42% 5 yr v 38% 5 yr
1996
Cognetti
SGC v S
38 v 58
44% 6.5 yr v 44% 6.5 yr
2011
SERIES
NEOADJUVANT
ADJUVANT
Table 1. Results of Randomized Trials of Neoadjuvant & Adjuvant Chemotherapy for Invasive Bladder Cancer
C: cisplatin
CMV: cisplatin-methotrexate-vinblastine
MVAC: methotrexate-vinblastine-Adriamycin-cisplatin
MVEC: methotrexate-vinblastine-epirubicin-cisplatin
CAP: intended regimen of cyclophosphamide-Adriamycin-cisplatin, but it was modified
GC: gemcitabine-cisplatin
RT: radical radiotherapy
S: surgery usually radical cystectomy
** many patients in the surgery-only arm did not receive chemotherapy at relapse thus this tested the utility of chemotherapy at some
time, rather than purely in an adjuvant context (if asking a true adjuvant question, patients receiving surgery-only would have been treated
at relapse with chemotherapy).
improvements in survival, confirmed by randomized

trials and a meta-analysis (Table 1) (7,39-42).
The International trial of neoadjuvant CMV was
designed to identify a 10% difference in longterm survival, but failed to do so in a cohort of
nearly 1000 randomized cases (39). It did achieve
a 6-7% difference survival, but was reported
as a negative trial initially as it did not achieve
the planned difference (39). Two years ago we
reported the final results of this study, showing a
sustained 6% 10 year survival benefit with a 16%
reduction in death from neoadjuvant CMV, with a
more obvious impact in surgical cases (40).
Although the North American Intergroup trial
of neo-adjuvant MVAC revealed a substantial
difference in median survival (6.4 years versus
3.8 years), the absolute improvement in longterm survival and potential cure rate was only
of the order of 7-8 percent (41), consistent with
the CMV study, and with a meta-analysis of
published randomized trials (42). Although a
modest improvement, it is real, and I believe that
this approach is the state-of-the-art in 2014.
Adjuvant chemotherapy
In several other cancers, classical adjuvant
chemotherapy, delivered after completion
of definitive local treatment, has produced a

statistically significant and clinically relevant
improvement in survival. In the past quarter century,
this strategy has been applied to the management
of bladder cancer, in the hope of duplicating this
outcome. However, randomized trials assessing
the utility of combination chemotherapy regimens
like the MVAC and CMV regimens or equivalent,
administered after radical cystectomy for patients
with pT3-4, N0-3 disease, have reportedly shown
improved disease-free survival (43-47). The problem
is that disease-free survival is not a sufficient
parameter of success in adjuvant studies, given the
potential for salvage therapy (48). In the traditional
models of adjuvant chemotherapy for solid tumors,
overall survival is the key outcome that indicates
success (48).
The group at the University of Southern California
conducted a clever study that was intended to
test the utility of adjuvant cyclophosphamidedoxorubicin-cisplatin after radical cystectomy;
although an apparent disease-free survival
benefit was reported, the study was marred by
failure to obey randomization rules, modifications
of chemotherapy, a focus on disease-free survival
and other procedural abnormalities (43).
Martie
June 2014
79
Review
In another widely quoted study, conducted in

Germany, there was an uneven distribution of
salvage chemotherapy, making the trial a test
of chemotherapy at any time after cystectomy,
rather than addressing the impact of early postcystectomy chemotherapy used as classical
adjuvant treatment (44-46). In this trial, patients
who were randomized to cystectomy-only
predominantly did not receive chemotherapy
at the time of relapse, thus making the trial
a test of the utility of chemotherapy per se,
rather than being a test of adjuvant therapy.
The interpretation of data in this study was
confounded by the addition of non-randomized
cases into the follow-up analysis (45) and admixture
of
intent-to-treat
and
received-treatment
analyses (46), the latter clearly being confounded
by case-selection bias.
The important study reported from Stanford
University was predicated on disease-free
survival, and thus was closed early by its Data
Safety and Monitoring Committee, and there
were insufficient cases to provide a meaningful
overall survival analysis (47). Unfortunately the
situation has been confused by a well-publicized
but flawed meta-analysis (42), which ignored the
various problems of individual published and
unpublished trials and grouped them together
into a comparison of observed versus expected
outcomes. This study erroneously concluded
that there is a statistically significant survival
benefit from adjuvant chemotherapy. While in
the future this may be proven to be correct, this
specific meta-analysis did not prove the point.
The EORTC has attempted to address this issue
in a well-designed, randomized trial, in which
standard local therapy has been compared
to standard local therapy plus the addition of
adjuvant chemotherapy.
Unfortunately this
important trial closed prematurely due to lack of
accrual, presumably because of preconceptions
of participating clinicians (or their patients)
about the true role of ancillary chemotherapy,
and it will henceforth be challenging to produce
level 1 data to resolve the issue.
Perhaps relevant to this issue is the study from
Stadler and colleagues (23), mentioned above. While
this study was not designed to address the utility of
adjuvant chemotherapy per se, and was restricted
to patients with mutant P53 tumors, stage pT1-2,
it is noteworthy that the patients who received 3
cycles of adjuvant MVAC did not appear to have
improved overall survival, compared with those
who were treated with surgery alone (23). Although
this may simply have reflected the population of
patients with P53-mutant urothelial cancer, this
study clearly did not provide any additional data to
support the routine use of adjuvant chemotherapy
for invasive bladder cancer. We still believe that
80
a randomized trial testing the use of adjuvant

chemotherapy is needed to resolve the issue, and
that adjuvant chemotherapy cannot be regarded
as standard-of-care in 2014.
Newer Approaches to Systemic Treatment

Combined with Local Therapy
Although some phase I-II studies focused
on novel agents used in the neoadjuvant or
adjuvant setting for bladder cancer have been
reported, there is very little level 1 information
about whether these innovations produce a real
survival benefit. In clinical practice, gemcitabinecisplatin has been used widely in association
with local therapy, either in a neoadjuvant or
adjuvant fashion, based on the thought that
the results achieved are similar to those from
MVAC; in reality, the only well-powered study
demonstrating this was in the metastatic setting,
and revealed a hazard ratio of 1.1, slightly
favoring MVAC (49).
To my knowledge, no definitive trial has proven
that gemcitabine-cisplatin provides a survival
benefit when added to definitive treatment in
either the neoadjuvant or adjuvant setting, nor
that it is equivalent to MVAC. The problems of
historical, non-randomized or under-powered
comparisons, including the potential for case
selection bias or follow-up bias, preclude any
valid statistical assessment of the published
data. In fact, Cognetti and colleagues, in a
randomized trial assessing the role of adjuvant
gemcitabine-cisplatin in one of two schedules,
reported non-significantly inferior survival from
the chemotherapy arm, compared to cystectomy
alone (H.R. 1.29, 95% CI 0.84-1.99, p=0.24) (50).
If I see a patient who is not sufficiently robust
to tolerate the MVAC or CMV regimens, I firstly
question whether that fact is likely to reflect limited
potential for safe radical cystectomy. If I conclude
that cystectomy is likely to be feasible and safe,
and that the MVAC regimen poses too much
risk because of its direct toxic side effects, I will
occasionally propose neoadjuvant gemcitabinecisplatin, after explaining carefully the limitations
of the published data.
Another regimen that was recently reported
in a randomized comparison against MVAC
for metastatic disease is the combination of
gemcitabine, cisplatin and paclitaxel (GCP)
(51)
. Although there was a modest increment
in response rate from GCP against metastatic
urothelial cancer, there was no significant
difference in survival. Nonetheless, a Spanish
cooperative group recently reported a survival
benefit from adjuvant GCP after cystectomy in
a presentation at the Annual Scientific Meeting
of the American Society of Clinical Oncology (52).
However, there are two important caveats to this
Derek Raghavan
observation (a) the same group initially reported

very impressive results with GCP for metastatic
disease in an early report at the ASCO meeting,
but subsequent follow up indicated a much less
impressive true result, indicating the importance of
mature follow-up and adequate sample size (53); (b)
I rarely implement data presented only at clinical
meetings without presentation as a peer-reviewed
manuscript, and it has been some years since the
initial presentation of this study without a followup peer-reviewed paper. There have been recent
reports of the use of targeted therapies, such as
erlotinib or lapatinib (targeting the epidermal
growth factor receptor), in patients with relapsed
disease, with disappointing results (54), and this
concept has been extended to the neoadjuvant
setting for invasive bladder cancer (55). These
studies represent clinical modeling and really are
not definitive, and it is not yet possible to make
any recommendations about the use of targeted
therapy in a neo-adjuvant context. That said, it
seems reasonable to consider the neoadjuvant
setting for clinical trial modeling, provided that
patients are not put at risk of unnecessary or
prolonged delay of definitive treatment.
Similarly, there is no published level 1 evidence
that confirms the utility of gemcitabine, the taxanes,
any novel platinum complexes in this context, and
thus no recommendations can be made about
their use, other than in the context of clinical trials,
at the present time. The risk in testing such novel
approaches is that an established paradigm, with
defined survival benefit, will be replaced by inferior
experimental therapy when cure is at stake.
The Future
It seems likely that molecular prognostication
and prediction will increasingly influence the
selection of treatment for invasive bladder
cancer in the future. In the treatment of

bladder cancer, we appear to have reached a
plateau with surgical and radiation techniques
to control local disease, and our progress
in cytotoxic chemotherapy has been slow
since the introduction of the taxanes and
gemcitabine.
However, there may be potential in leveraging
the panoply of targeted therapies, provided
that this is done in well-structured clinical trials
that are designed to avoid losing the gains that
we have won since 1980.
Of importance, we must be mindful of the
promiscuity of some targeted therapies in their
interaction with their purported targets, and
we should be cautious in the use of Bayesian
randomized discontinuation designs, which
may incorrectly omit agents that have modest
activity, especially if it is manifested after a
time lag.
Despite the failure of the P53 trial to
achieve its goals (23), its study design may
provide a useful paradigm for future research.
The idea of designing trials based on defined
gene targets makes sense, but these studies
may require additional patient information
to improve recruitment and compliance. It
also will be important to remind patients and
physicians about the progress that has been
made, to avoid nihilism and a return to the
ways of the past, and also to emphasize the
importance of randomized clinical trials in
demonstrating real, but incremental, progress.
In the absence of a quantum leap forward,
clinical trials will allow us to improve survival,
unlike the myriad of under-powered phase I-II
trials of the past 20 years.
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Review
The Endocrine Phenotype in Ovarian Tumors

Mara Carsote1,2*, Valentin Radoi1, Catalina Poiana1,2
1. Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
2. Department of Pituitary and Neuroendocrine Diseases, C.I.Parhon National Institute of Endocrinology, Bucharest, Romania
Corresponding Author: Mara Carsote MD, PhD
C.I.Parhon National Institute of Endocrinology, Bd. Aviatorilor no. 34-36, Bucharest, Romania
Tel.: 021 317 2041
E-mail: carsote_m@hotmail.com
Open Access Article
Abstract
Keywords:
Sertoli-Leydig cell
tumor, gonadoblastoma,
teratoma, ovarian tumor,
ovarian carcinoid
Received:
13 May 2014
Accepted:
21 May 2014
Cite this article:

Carsote M, Radoi V,
Poiana C. The endocrine
phenotype in ovarian
tumors. Rom J Oncol
Hematol. 2014; 2(2):84-89.
84
The ovarian tumors represent a challenging subject in actual

medicine because of the new clinical, genetic, and immunochemical
features which help us better understand them. In this paper we will
mainly focus on the ovarian tumors that are associated with endocrine
anomalies comprising an endocrine phenotype. The most important
are the sex cord-stromal cell tumors. They gain the enzymatic
and protein equipment in order to induce an excess of estrogens
that are associated with menses anomalies and uterine bleeding
in menopause or androgen excess that induces the virilization
syndrome. If the onset of the endocrine activity is in a juvenile
population, the endocrine phenotype is dominated by precocious
puberty. Another type of tumors are the germ line cell tumors,
mostly the teratoma. The most interesting aspects of endocrine
manifestations are the struma ovary and the ovarian carcinoid.
The gonadoblastoma associates sex reversal since the majority
of the tumors associate both the presence of the Y chromosome
and the female phenotype. Finally, this paper is an argument for a
multidisciplinary approach in ovarian tumors.
Introduction
The ovarian tumors comprise a wide area of
diseases with various aggressive profiles. The
endocrine involvement is related not only to the
good or bad function of the ovaries, but it is also
related to the complex genetic syndromes or
karyotype anomalies that might bring together
many endocrine disturbances, not only strictly
regarding the ovarian function.
The most important aspect in this complex and
dynamic field of interest is the multidisciplinary
approach.A patient might be seen by a gynecologist,
an endocrinologist, a surgeon, a radiologist, or an
oncologist, but the most correct approach is an
adequate communication and sharing of opinions
between more than one specialist. Nevertheless,

the first who might come into contact with a female
subject displaying an ovarian tumor might be the
pediatrician, the general practitioner or the internal
medicine specialist based on the large area of ages
that associate ovarian tumors. After the removal of
the tumor, the most important aspect that actually
sets the management is the histological report.
Based on this, the endocrinologist or gynecologist,
on one side, or the oncologist, on the other side,
will choose the adequate strategy for the subject
(Figure 1).
The classification of ovarian tumors suffered
a dynamic process of being brought up to date
during the last years (1). The criteria to be taken
Carsote M, Radoi V, Poiana C
Figure 1. The pyramid
with different specialists

that may be involved in
the management of a
case with ovarian tumor
into account are mainly histological, including the

malignant features (2). The term of ovarian cancer
is classically related to the surface epithelium but all
the others tumors (including those with endocrine
phenotype) may embrace a malign behavior (3).
The category of the epithelial ovarian tumors
(like those with mucinous, serous or endometroid
cells, carcino-sarcoma mixed or undifferentiated
carcinomas) includes very aggressive tumors (4).
They are correlated in various ways with all kind
of risk factors, including hormonal panel such as
oral contraceptives, genetic anomalies, patients
age, and so on (5-7). Their frequency depends on
the group of subjects analyzed (8,9). These tumors
have less endocrine aspects on admission and
this group will not be discussed in this paper (10).
The endocrine phenotype that will be taken into
account in this article will be mainly focused on sex
cord-stromal tumors, germ cell tumors, and also
the gonadoblastoma related to the switched
(opposite to the genetic sex) phenotype (endocrine
but not only) to the karyotype. We mention that
regardless of the endocrine features and the
oncologic profile, each of the ovarian tumors may
associate the mass syndrome caused by the tumors
themselves (Figure 2).
General data
The sex cord-stromal tumors

The ovarian tumors which are most frequently
associated with endocrine anomalies that might
become clinically manifested are sex cord-stromal
tumors. They embrace a great variability of signs
and symptoms, and even in the same patient the
clinical appearance might change during time.
The endocrine phenotype generally includes
precocious puberty, menses anomalies like uterine
hemorrhage, meno-metrorrhagia, vaginal bleeding
after menopause, and virilization syndrome. The
adult onset masculine phenotype is mainly caused
by two types of tumors: ovarian and adrenal
(like adrenal carcinoma and exceptional adrenal
adenoma) (11). It consists of hirsutism (evaluated
based on the Ferriman-Gallwey score), alopecia,
the increase of muscle mass, the change of voice,
the android proportions of the body, and also
biochemistry blood changes such as high levels of
uric acid, increased number of red blood cells and
hypercholesterolemia (12). The only external genital
organ that responds to androgens after birth is the
clitoris and clitoromegalia might be registered.
All the symptoms and signs related to the tumor
androgens are reversible during time with different
June 2014
85
Review
Figure 2. Abdominal
mass in a 82 year old
female: ovarian tumor
of 19 centimeters (the
histological report
pointed towards
a benign cyst)
timing depending on cause, organs and age of the

patient. Sometimes, the secondary amenorrhea
caused by hyperandrogenism that suppresses
the gonatropin levels might mimic menopause (13).
Apart from the endocrine phenotype associated
with the ovarian tumor, other anomalies might
be registered. The risk of a second neoplasia
apart from the first ovarian tumor depends on the
underlying cause, the patients age, the use of oral
contraceptives, radiotherapy, genetic background
and so on (14). For example, we previously reported
a case of thyroid cancer and androblastoma but
it is difficult to appreciate if this was an incidental
finding (13).
The sex cord-stromal tumors may also display
non-specific features and many times the
diagnostic is retrospective, after the histological
examination of the removed ovary. The recent
approach includes a detailed immunochemical
analysis that may highlight more features of
the tumor and tumors management (15). One
of the most useful combination is the assay of
SF1 (steroidogenic factor 1) and FOXL2 which
may be positive in sex cord-stromal tumors and
CK AE1/AE3 (cytokeratin) or EMA (epithelial
membrane antigen) which are more suggestive
for epithelium, and rather negative in sex cordstromal tumors. Nevertheless, mixed phenotypes
regarding the immunochemistry panel might be
registered (16-18).
The main types of sex cord-stromal tumors are
the tumors associating granulosa cells, fibromas,
tecomas, sclerozating stroma tumors, annular
tubule tumors, tumors with Sertoli-Leydig cells,
with steroid cells, and mixed or undifferentiated
neoplasia (15).
The granulose cell tumors have an adult type
(which represents 95% of cases) and a juvenile
type (5% of cases). One of the underlying
endocrine mechanisms in ovarian tumors
presenting granulose cells is the Anti-Mullerian
hormone (AMH) that inhibits the growth of
tumor cells by activating the apoptosis after
86
the link with the AMH type II receptor from

granulose cells (19). Others oncogene related
proteins have been found such as YAP (yesassociated protein) (20,21). The adult group of
granulose cell tumors represents the most
frequent tumors from the entire group of sex
cord-stromal tumors (comprising almost two
thirds). The median age at diagnosis is 48 years
of life. The histological features include solid
or partial cystic (probably with hemorrhage)
appearance. The immunochemistry might
find positive reaction for calretin or CD99. The
aggressive behavior is reported in some cases
(recurrences or local metastases) (15,22). This
makes lifelong follow-up of a patient diagnosed
with such a tumor mandatory (23). The endocrine
phenotype in granulose cell tumors varies from
mild symptomatic cases (or even without any
symptoms) to precocious puberty (in pre-pubertal
state), menses anomalies due to the hyperestrogenic state in subjects of reproductive age
and in post menopause endometrial hyperplasia
(with secondary bleeding) is seen. Thus, the
endocrine aspects are strongly related to the age
of the patient. This type of tumors is regarded as
the most estrogenic type of ovarian tumors (15,24).
Independent of this aspects, the tumor itself may
cause an abdominal mass syndrome, or the cyst
part of the tumor may cause hemoperitoneum
(one tenth of cases) or even ascites (25). One in ten
tumors is completely asymptomatic (regarding
the mass syndrome and the endocrine anomalies)
(26)
. The juvenile tumors may also associate
recurrences or metastases (even a case of cancer
related hypercalcemia has been reported) while
the endocrine phenotype is quite suggestive
because of abnormal endocrine activity in early
years of life: girls before menarche and young
(teenager) women (15,27). The most frequent types
of infantile onset in sex cord-stromal tumors
were found to be, according to a meta-analysis:
juvenile granulose cells tumors, sclerozating
stromal tumors, Sertoli-Leydig cell tumors, and
fibromas (15,28). Despite the high increase of

the hormonal activity in granular cell tumors,
hormonal replacement therapy after the removal
of the tumor (in case of bilateral ovarectomy) is
necessary but even if this is applied, there are
limited prospective lifelong studies regarding
this issue (29).
The fibromas have a median age at onset of 42
years and may have recurrences. The histological
groups are cellular fibroma and fibrosarcoma
(30)
. Mixed forms comprising both thecomas and
fibromas have been reported (31). The thecomas
may also associate an aggressive profile with
recurrences or metastases; the histological forms
are classical and luteinized (32,33). The endocrine
phenotype in thecomas is mainly related to
the excess of estrogens (like abnormal uterine
bleeding including in menopause, abnormal
menses and endometrial hyperplasia) and
exceptional with excess of androgens (34,35).
The sclerosing stromal tumors are extremely
rare and are mostly seen in the second or third
decade of life. The tumors have a low aggressive
profile. The symptoms are related to the mass
syndrome and with anomalies of the menses. The
clue of the endocrine phenotype is abnormal
hormonal activity at extreme ages in pre
menopause or after menopause. The endocrine
secretion is related to either excess of estrogens
or of androgens (36,37).
The annular tubule ovarian tumors have two
forms: one associates Peutz Jeghers syndrome
(median age at diagnosis is reported at 27
years; 1/3 of cases), and another which does not
associate the Peutz syndrome and has an older
age at incidence (the median age at diagnosis
is reported at 34 years; 2/3 of cases). In this last
situation, half of the cases embrace an endocrine
phenotype with hyper-estrogenism. The signs
(that are caused by an excess of estrogens) vary
depending on the subjects age (as in the case of
other histological sub-types) (38-40).
The Sertoli-Leydig cell tumors have different
histological types: well, medium and low
differentiated, retiform type, with heterologous
elements, only with Sertoli cells or stromal Leydig
cells (41). The main types of cells (apart from various
heterologous cells) are Sertoli cells and Leydig
cells (both with virilization potential), fibroblasts
or epithelial cells (possible in a net display) (Figure
3) (42). This group of tumors represents 0.5% of all
ovarian tumors; they are mostly seen in the third
decade of life, with a median of 35 years for the
well differentiated type (43,44). One of the newest
mutations reported is DICER 1 which acts as an
endoribonucleasis (45). The well differentiated
Sertoli-Leydig cell tumors represent one tenth of
all Sertoli-Leydig tumors. Usually, they present as
a solid unilateral tumor with a medium diameter
of 5 up to 6 centimeters (46). Some correlations

with genital tract anomalies have been reported.
The medium or low differentiated Sertoli-Leydig
cell tumors may be bilateral in 2% of cases.
Their maximum diameter has been found to
be of 15 centimeters (46). The Sertoli (stromal)
cell tumors have various dimensions (up to 10
centimeters). The median age of incidence of
30 years has been reported. They display mostly
an estrogenic phenotype, while the androgen
phenotype is seen in only 1/3 up to 1/5 of
cases. The prognosis is correlated to atipia or
the high number of mitoses (47). Nevertheless,
the tumor might be completely asymptomatic
and its diagnostic may be incidental at a routine
checkup. In such cases, we encourage the term
of ovarian incidentaloma based on an analogy
with adrenal or pituitary incidentaloma. Yet, the
management of the ovarian tumors is always
the removal of the tumor while in pituitary
incidentalomas and in selected cases of adrenal
incidentaloma the adequate management is
only the close follow-up of the tumor (48,49). The
tumors with heterologous elements associate all
kinds of cells (most frequently mucin producing
epithelium, but also muscle cells or fat cells etc.)
among the Sertoli-Leydig cells. They are different
from teratoma because here the non-ovarian cells
are fewer than in teratoma (50). The steroid cell
tumors may be well or low differentiated. Four
out of 10 cases associate a virilization syndrome.
Extremely rare, an estrogenic phenotype or even
Cushings syndrome has been reported (51). The
endocrine production consists in androstendion,
-hidroxyprogesteron, testosterone (52). Ten
percent of Sertoli-Leydig cell tumors cannot
be classified and display a non-specific
endocrine and non-endocrine phenotype. These
mixed forms should be evaluated based on
immunochemistry and genotype such as DICER1
mutations (53).
The germ cell tumors
The class of germ cell tumors includes tumors
with unipotent germinal cells (disgerminomas)
and pluripotent germinal cells (teratoma,
yolk
sac
tumor, embryonal
carcinoma,
choriocarcinoma, polyembryoma or mixed
tumors) (54). Disgerminomas represent 1% of
ovarian cancers and may be bilateral. They are
mostly seen at extreme ages. Ten percent of
these tumors are hCG producers. Endocrine
anomalies are estrogen or androgen excess
(55)
. The neuroendocrine markers are LDH and
neuron specific enolase. Extremely rare, they are
associated with high levels of calcium or prolactin
(56)
. Teratomas may be mature or immature
(benign or malign). They are most frequently
seen in young females. The clinical phenotype
may be absent or related to the heterologous
June 2014
87
Review
elements (57). As pointed by the Greek word

teratos meaning bizarre they behave in
surprising ways. For example, the peritoneal
gliomatosis is the implant of neural adult cells
from an ovary immature glial cell teratoma (58). The
struma ovari represents teratomas with thyroid
tissue. They are usually benign, unilateral tumors
(59-61)
. Mostly, these are seen in the fifth decade of
life. The mass syndrome is registered in one fifth
of the cases (59-61). Fifteen percent of teratomas
may associate thyroid tissue but, in struma ovari,
by definition, 50% of the tumor is comprised
of thyroid cells. The thyroid pattern is follicular,
papilar or mixed. Thyroid cancer in this tissue
is very rare. Most of the times the thyroid tissue
is hypofunctional and rarely hyperfunctional (5961)
. The ovarian carcinoid is very rare. The true
carcinoid syndrome is very rare. The heterologous
elements are neuroendocrine cells. The pattern
is insular, trabecular, mucinous or mixed. Usually
the tumors are very aggressive, as pointed by
the Ki67 proliferation marker (62-64).
The gonadoblastoma
The gonadoblastoma is a mixed tumor with
germinal cells, sex cord-stromal cells etc.
Some genetic syndromes have been reported
in association with gonadoblastoma such as
Apert or Fraiser. The clue in understanding the
gonadoblastoma is that in 90% of cases the Y
chromosome is present. The clinical (nevertheless)
phenotype is switched to the karyotype meaning
that 4 out of 5 cases have a female phenotype while
the Y chromosome is present in Turner mosaicism
(such as 45 X0/46 XY) or Swyer syndrome (the
mutation of the SRY gene) (65,66).
Figure 3. The types of cells in Sertoli-Leydig tumors
Conclusion
The area of ovarian tumors underlying
endocrine anomalies is related to the sex cordstromal tumors that associate an estrogenic or
androgenic phenotype, both with effects in
puberty. In very young ages, the endocrine
germ line cell tumors are struma ovary and
ovarian carcinoid. We would also mention the
inversed phenotype in gonadoblastoma which
associates the Y chromosome and the female
phenotype.
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62. Amano Y, Mandai M, Baba T, Hamanishi J, Yoshioka Y, Matsumura N, Konishi
I. Recurrence of a carcinoid tumor of the ovary 13 years after the primary
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Molecular mechanisms implicated in citostatic resistance in cancer cells fro m metastatic breast cancer
Molecular mechanisms implicated in

citostatic resistance in cancer cells from
metastatic breast cancer
Mecanisme moleculare implicate n rezistena
la chimioterapie n celulele neoplazice din
cancerul mamar metastatic
Daniela Zob*, Dana Lucia Stnculeanu, Iuliana Gruia
1. Medical Oncology I, Institute of Oncology, Bucharest, Romania
2. Research, Institute of Oncology, Bucharest, Romania
Corresponding Author: Daniela Zob
Medical Oncology I, Institute of Oncology, Bucharest, Romania, Fundeni Street, no. 252, Sector 2, Bucharest, Romania
Tel: +40021 227 10 00 Fax: 40021 318 32 62
E-mail: danielazob@yahoo.com
Open Access Article
Abstract
Keywords:
breast cancer,
chemotherapy,
resistance,
molecular mechanisms
Received:
13 February 2014
Reviewed:
05 May 2014
Accepted:
28 May 2014
Cite this article:

Zob D, Stnculeanu
DL, Gruia I. Molecular
mechanisms implicated
in citostatic resistance
in cancer cells from
metastatic breast cancer.
Rom J Oncol Hematol.
2014; 2(2):90-97.
90
The purpose of chemotherapy is to prevent cancer cells from

multiplying, invading and metastasizing. The majority of cytotoxic
drugs are active on multiplying cells - cancer cells and normal
dividing cells. Chemotherapy could be used with curative intent,
but, in clinical practice, curative intent is limited by citostatic drug
resistance and toxicity to normal tissues.
Chemotherapy resistance could be divided in intrinsic
resistance - resistance that appears before any exposure to
chemotherapy, and extrinsec resistance - resistance developed
during the treatment, or inductible resistance in which cancer
cells suffer genetic and epigenetic modifications that lead to
chemoresistance. Resistance can be related to: pharmacological
factors such as absorption, improper activation, metabolisation
and rapid excretion of cytotoxic drugs or alteration of transport
proteins - (resulting in a low level of the drug); and physiological
factors: metastasis in sanctuaries; and cellular factors: a
decrease in drug accumulation (low influx, high efflux), alteration
of cellular metabolism (increase in degradation, low activation);
citoplasmatic-nuclear inactivation (glutathione, metalotionine,
proteins?), DNA repair, alteration in cellular targets.
Although cellular mechanisms implied in citostatic resistance have
been elucidated in culture cells, their clinical relevance is less clear.
In this article we intend to present a short review of recent data from
the literature regarding molecular and cellular mechanisms with a
less known clinical relevance compared to the pharmacological one
in relation with chemotherapy resistance.
Zob D, Stnculeanu DL, Gruia I
Rezumat
Cuvinte-cheie:
Cancer mamar,
chimioterapie, rezisten,
mecanisme moleculare
Scopul tratamentului citostatic este prevenirea multiplicrii celulelor canceroase i a fenomenului de invazie i metastazare. Majoritatea agenilor
citostatici i exercit efectul asupra celulelor n diviziune, afectnd cu
preponderen celulele tumorale, dar i celulele normale aflate n diviziune. Dei aparent chimioterapicele ar avea aciune curativ, n practica
curent, aciunea curativ este diminuat de prezena rezistenei la tratament i de toxicitatea asupra esuturilor normale.
Rezistena la chimioterapie poate fi divizat n rezisten intrinsec
rezistena aprut naintea oricrei expuneri la citostaticul respectiv, sau
extrinsec - rezistena dezvoltat pe parcursul tratamentului, sau inductibil
- n care celulele canceroase sufer modificri genetice sau epigenetice,
care duc la chimiorezisten. Rezistena poate fi legat de factori farmacologici precum absorbia, activarea deficitar, metabolizarea i excreia
rapid a citostaticului sau alterarea proteinelor de transport, (rezultnd n
nivel sczut de medicament), fiziologici - metastazarea n sanctuare i factori celulari: scderea acumulrii citostaticului (influx sczut, eflux crescut),
alterarea metabolismului celular (creterea degradrii, scderea activrii),
inactivarea citoplasmatic-nuclear (glutation, metalotionine, proteine?),
repararea ADN, alterarea intei celulare.
Chiar dac mecanismele celulare implicate n rezistena la chimioterapie
sunt elucidate pe culturi celulare, relevana clinic este mai puin clar.
n cele ce urmeaz vom prezenta o actualizare a principalilor factori celulari i moleculari implicai n rezistena la chimioterapie, cu relevan clinic
mai puin cunoscut comparativ cu cea farmacologic.
Abreviations:
Fasl - ligand FAS
FasR - CD 95-receptor Fas
Bak - antagonist killer Bcl2 omolog (Bcl-2
monologus antagonist killer)
Bax - proteina x asociat Bcl (Bcl associated x
protein)
Cyt C - citocrom C
SMAC/DIABLO - homolog Diablo
IAPs - proteina inhibitoare a apoptozei (inhibitor
of apoptosis proteins)
C9 - caspaza 9
C3 - caspaza 3
C7 - caspaza 7
NFkB - nuclear factor Kappa- (light chain enhancer of activated B cells; face parte din categoria factorilor de transcripie cu aciune rapid)
STAT - factor de transcripie (signal transducer
activator of transcription)
GADD45 - gena - implicat n rspunsul la stres
(Growth Arrest and DNA Damage)
P21/WAF1 - inhibitor kinazic ciclin dependent
(cyclin dependent kinase inhibitor)
ADN - acid dezoxiribonucleic
ATP - adenozin trifosfat
ADP - adenozin difosfat
ABC - caseta care leag ATP (ATP binding cassette)
Pgp - P-glicoproteina
MRPs - proteine de rezisten multimedicament
(multidrug resistance proteins)
ABCA - caseta care leag ATP (ABCG-ATP binding cassette A-G)

TMD - domeniu transmembranar (transmembranar domain)
NBD - domeniu de legare a nucleotidelor (nucleotide binding domain)
GSH - glutation
MRP1- protein de rezisten multimedicament
1 (multidrug resistance protein 1)
BCRP - protein de rezisten n cancerul mamar
(breast cancer resistance protein)
MDR - rezisten multimedicament (multidrug
resistance)
Non ABC protein MDR - proteine MDR transportoare, altele dect ABC implicate n rezistena multimedicament
RhoGTP-aze - este o familie de proteine G mici
de semnalizare, GTP-aze i este o subfamilie a superfamiliei Ras
HSF - regiune colorant omogen (homogenous
staining region)
DHR - dihidrofolat reductaz (dihidrofolat reductase)
ARNm - ARN mesager
VP16 - vepesid
BSO - aminoacid butionin sulfoxim sintetic
mTHF - acid levomefolic (methyltetrahydrofolate)
5FdUMP - monofosfat fluorodeoxiuridin (fluorodeoxyuridine monophosfhate)
5FTP - flourouridin trifosfat (flourouridine triphosphate)
June 2014
91
Review
92
c-myc - gena reglatoare c-Myc localizat pe cromozomul 8

Bcl2 - familia Bcl 2; proteine reglatoare ale apoptozei (Bcell lymphoma 2)
Bcl-XI - molecul transmembranar n mitocondrie, membru al familiei de proteine Bcl-2 (B-cell
lymphoma-extralarge)
P53 - proteina supresoare tumoral numit p53
TP53 - gena care codific p53
P14 - regulator pozitiv p53
Akt - regulator negativ p53
ATM - mutaie ataxie-telangiectazie (ataxia telangiectasia mutation)
ART - ATM i Rad 3 legate
ADN-PK protein-kinaza ADN dependent

(DNA-protein kinase)
Gena mdm2 - este un regulator negativ al p53
(mouse double minute 2 homolog)
Bax - protein care iniiaz direct apoptoza
SAPK protein-kinaza activat de stres
(stress activated protein-kinase) numit
i JNK (c-jun N terminal protein-kinase a
crei activare este necesar pentru moartea
celular)
MAPK protein-kinaza activat mitogen (mitogen activated protein-kinase)
ERK - kinaz reglat de stimulul extracelular (extracellular stimulus regulated kinase)
Cancerul mamar este neoplazia cu incidena cea

mai mare la sexul feminin n Romnia, conform
estimrilor WHO (International Agency for
Research on Cancer- EUCAN) 2012 (25,22% din
toate neoplaziile diagnosticate anual sunt cancere
mamare) i cu cea mai mare mortalitate (16,74%
n Romnia n 2012). Incidena brut n Uniunea
European este de 94.2/100.000 femei, iar
mortalitatea este de 23.1/100.000 femei. n ciuda
faptului c prognosticul cancerului mamar s-a
ameliorat simitor n ultimii ani, un numr mare de
paciente prezint evoluie de boal, rezistena la
diferitele citostatice reprezentnd principala cauz
de eec terapeutic n cazul majoritii pacientelor
cu cancer mamar metastatic.
Scopul tratamentului citostatic este prevenirea
multiplicrii celulelor canceroase, a fenomenului de
invazie i metastazare (1,2). Majoritatea agenilor citostatici
i exercit efectul asupra celulelor n diviziune, afectnd
cu preponderen celulele tumorale cu diviziune
necontrolat, dar i celule normale aflate n diviziune.
Dei aparent chimioterapicele ar avea aciune curativ,
n practica curent, aciunea curativ este diminuat de
prezena rezistenei la tratament i de toxicitatea asupra
esuturilor normale. De aici apar obstacolele n utilizarea
tratamentului citostatic: rezistena la medicament i
toxicitatea asupra esuturilor normale.
Didactic, rezistena la chimioterapie poate fi divizat
n rezistena intrinsec - naintea oricrei expuneri
la citostaticul respectiv, sau extrinsec - dobndit
pe parcursul tratamentului, sau inductibil - n care
celulele canceroase sufer modificri genetice sau
epigenetice, care duc la chimiorezisten. Rezistena
poate fi legat de factori farmacologici precum
absorbia (1), activarea deficitar, metabolizarea (3)
i excreia rapid a citostaticului (4) sau alterarea
proteinelor de transport, fiziologici - metastazarea n
sanctuare (5) i factori celulari: scderea acumulrii
citostaticului (influx sczut (6), eflux crescut (7)), alterarea
metabolismului celular (creterea degradrii,
scderea activrii), inactivarea citoplasmaticnuclear (glutation, metalotionine, proteine?),
repararea ADN, alterarea intei celulare (figura 1).
n cele ce urmeaz vom prezenta o actualizare

a principalilor factori celulari i moleculari, cu
relevan clinic mai puin cunoscut comparativ
cu cea farmacologic. Chiar dac mecanismele
au fost clarificate n culturile celulare, relevana
acestora n practica clinic e mai puin clar.
Excluderea:
1.a. Sechestrarea - Sechestrarea intracitoplas
matic a citostaticelor a fost corelat cu prezena
citoplastelor. Acestea sunt vezicule intracelulare
cu membran proprie, n care sunt concentrate i
sechestrate anumite citostatice n celulele tumorale
(ex. doxorubicina). Antraciclinele i alcaloizii de vinca
(baze slabe) pot fi captate de vezicule endozomale
i lipozomale cu un pH acid i apoi eliminate prin
fuziune cu membrana plasmatic. Acest mecanism
determin imposibilitatea efecturii activitii
citotoxice a citostaticelor respective.
1.b. Exportul activ sau creterea efluxului
celular. Creterea activitii pompelor de eflux
dependente ATP determin scderea concentraiei
intracelulare a anumitor citostatice (doxorubicin,
daunorubicin, vinblastine, vincristine i paclitaxel).
Medicamente precum antraciclinele i taxanii,
care intr n celul prin difuziune pasiv, pot fi
exportate activ transmembranar via transporteri
ATP binding cassette (ABC), transporteri care
includ Pgp (P-glicoproteina) i MRPs (multi drug
resistance proteins) (8,9).
Transporterii ABC utilizeaz energia rezultat
din hidroliza ATP-ului pentru realizarea efluxului
i pot fi divizai n trei categorii funcionale: 1.
Importeri- mediaz influxul nutrienilor n celul ex. aminoacizi, glucide i ioni; 2. Efluxeri - pompe
care export toxine i medicamente din celul;
3. Transporteri implicai n procesul de translaie
i reparare a ADN-ului. Pn n prezent au fost
identificate 49 de gene ABC divizate n 7 subfamilii
(ABCA- ABCG) (tabelul 1).
Proteinele familiei ABC sunt caracterizate prin
dou domenii distincte: domeniul transmembranar
Zob D, Stnculeanu D, Gruia I
Figura 1. Principalele mecanisme implicate in rezistenta la chimioterapie. Adaptat dup (17)
(TMD- transmembranar domain), cunoscut i ca

membrane spanning domain, i domeniul care
leag nucleotidele (NBD - nucleotide binding
domain). TMD recunoate o varietate de substraturi
i sufer modificri conformaionale pentru a le
transporta transmembranar. Secvena aminoacizilor
i structura TMD sunt variabile, reflectnd diversitatea
chimic a substraturilor ce pot fi translocate. NBD
sau ATP - binding cassette (ABC) este localizat n
citoplasm i are o secven i structur fix unde se
produce legarea de ATP (11).
P - glicoproteina (PGP)/ ABCB1
PGP are o distribuie tisular larg (12) i a fost primul
transportor ABC identificat ca fiind supraexprimat
n liniile celulare de cancer mamar MDR (multidrug
resistance). Gena care codific Pgp este multidrug
resistence 1 MDR1 - denumit i ABCB1 (13). PGP
are 12 domenii transmembranare i dou situsuri
de legare a ATP. Ali transporteri cu structura similar
sunt MDR4, MRP4, MRP5 i MRP7. Este localizat la
nivelul membranei apicale a celulelor epiteliale i este
implicat n exportul transmembranar al compuilor
neutri i cationici hidrofobi, precum: vinblastin,
vincristin, doxorubicin, daunorubicin, etoposid i
paclitaxel. Pentru transportul transmembranar via
PGP, extracia citostaticului apare frecvent direct din
partea citoplasmatic a dublului strat lipidic (14).
Proteina asociat MDR (MRP1) este exprimat
n multe organe i tipuri celulare (vezi tabelul 1),
iar studiile au demonstrat c supraexpresia MDR1
face celula rezistent la o varietate de substane
citostatice, printre care i doxorubicin(15).
Pentru multe medicamente, transportul mediat
MRP1 este stimulat de prezena glutationului.
Spre deosebire de PGP, care are tendina de a fi
localizat la nivelul membranei apicale a celulelor
epiteliale, MRP1 este localizat bazolateral. MRP 1
are o structur similar cu PGP i are nevoie de dou

molecule ATP ca surs energetic, dar situsurile
de legare a nucleotidelor 1 i 2 (NBD1 i NBD2)
difer n afinitate pentru ART. Substratul se leag
de domeniul transmembranar MRP1, cauznd
o modificare conformaional a proteinei, care
iniial induce legarea ATP de NBD1. Urmtoarele
modificri conformaionale cresc legarea ATP la
NBD2. Cnd ambele NBD1 i NBD2 sunt ocupate,
substratul legat este transportat extracelular. ATP
legat la NBD2 este hidroxilat i se elibereaz
subsecvent ADP de la NBD2 i ntoarce parial
MRP1 la conformaia original, facilitnd eliberarea
legrii ATP i completarea ciclului NBD1 (7).
Breast Cancer Resistance Protein (BCRP)/
ABCG2 este exprimat ntr-o varietate de tumori i
este asociat cu rezistena la o varietate de ageni:
mitoxantron, camptotecin, antracicline i antifolai
(16)
. Spre deosebire de PGP i MRP1, proteina BCRP
conine numai un domeniu transmembranar i un
domeniu de legare a nucleotidului. Mecanismul
de transport facilitat de BCRP nu a fost investigat
n detaliu. Unele dintre celulele stem i celulele
tumorale n mediu hipoxic ar putea fi protejate de
agenii citostatici prin creterea expresiei BCRP
indus de hipoxie.
Non ABC protein MDR este un alt transporter
conjugat GSH, Ral-binding protein 1 (RLIP76/
RALBP1), o protein Ral reglat care aparine familiei
Rho GTPaze. RLIP76 membranar funcioneaz ca
o pomp de eflux multispecific pentru agenii
antitumorali - alcaloizii de vinca i antracicline
(9- REDOX). RLIP 76 pare s fie o protein de
rspuns la stres, care ofer protecie mpotriva
stresului oxidativ indus de aceti compui. Multe
rapoarte au descris asocierea proteinei rezistente
pulmonare (LRP - lung resistance protein) cu
June 2014
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Gena
Proteina
esutul
Citostaticele exportate de transporter
ABCB1
PGP/
MDR1
Intestine, ficat, rinichi, placent, barier

hematoencefalic, majoritatea esuturilor
ADR, VP 16, VBL, PTXl
ABCC1
MRP1
Toate esuturile
ADR, VCR, VP16, MTX
ABCC4
MRP4
Prostat, testicul, ovar, intestine, pancreas,

plmn, rinichi, majoritatea esuturilor
ABCC5
MRP5
Majoritatea esuturilor
6-mercaptopurin, 6-tioguanin i
metaboliii i MTX
6-mercaptopurin i 6-tioguanin i
metaboliii
ABCC10
MRP7
ABCC11
MRP8
ABCC12
MRP9
Sn, testicul, creier, os, ovar
Necunoscute
ABCG2
BCRP
Ficat, sn
DOX, IRI, MTX
Expresie sczut n toate esuturile cu

excepia pancreasului
Expresie scazut n toate esuturile cu
excepia rinichiului, splin, colon, creier
5-flourouracil
Tabelul 1. Transporterii ABC i implicarea lor n rezistena la citostatice prin scderea concentraiei intracelulare (10)
fenotipul MDR non Pgp mediat n linii celulare
canceroase umane.
1.c. Scderea influxului - prin mutaii inactivatoare
sau scderea expresiei moleculelor carrier (17).
Influxul celular al citostaticelor hidrosolubile
apare de-a lungul membranei plasmatice i este
produs de carrieri cunoscui a transporta nutrieni
sau alte molecule eseniale cu greutate molecular
mic i de procesul de endocitoz nespecific (18) sau
mediat de receptor (pinocitoz). Selecia celulelor
rezistente la citostaticele care intr n celul via
receptori sau transporteri rezult din mutaiile care
elimin/modific aceste molecule de suprafa
celular, ca de exemplu rezistena la metotrexat
prin mutaie i/sau scderea transporterilor de
folai: folate binding protein, rezistena la analogii
de nucleozide, prin mutaii ale unor transporteri
specifici de nucleozide. Unii dintre agenii citostatici
noi ca imunotoxinele care se leag de receptorii
de pe suprafaa celulei nu pot omor celula dac
nu sunt internalizai mai ales pe calea endocitozei
receptor-mediat. Citostaticele hidrosolubile au
o afinitate crescut pentru transportatori carrier
de nutrient i rar se acumuleaz celular - exemplu
cisplatinul, 8-azaguanida i 5-fluorouracilul.
Modificarea intei citostaticului. Modificri ale
situsului de legare a citostaticelor (19) apar n cazul
rezistenelor la taxani, metotrexat, antracicline.
Rezistena la taxani poate aprea att prin creterea
efluxului celular via Pgp, ct i prin alterarea expresiei
proteinelor asociate microtubulilor, mutaii ale
tubulinei sau expresia alterat a isoformei a tubulinei,
mutaii ale tubulinei, supraexpresia III tubulinei
sau alterarea situsului de legare. Supraexpresia III
tubulinei a fost asociat cu rezistena intrinsec i
dobndit la taxani n diferite linii celulare (20, 21).
Celulele rezistente la Metotrexat prezint cro
mozomi minusculi (double-minute) sau HSR
94
(homogenous staining regions) ca mrturie

a amplificrii genice (mecanism de activare a
protooncogenelor) a enzimei dihidrofolat-re
ductaz (DHFR), care este inta atacului pentru
metotrexai. Se pot cita i alte exemple de modificri
enzimatice care reprezint alterri cantitative ale
timidilat-sintetazei (enzim implicat n rezistena
la 5-fluorouracil) sau ale topoizomerazelor.
Topoizomerazele sunt enzime nucleare care
catalizeaz modificri n structura secundar,
teriar i cuaternar a ADN, cataliznd clivarea
tranzitorie monocatenar (topoizomeraza I) sau
bicatenar (topoizomeraza II) a ADN. Citostaticele
antitopoizomerazice permanentizeaz complexele
clivabile ADN-protein, perturbnd repararea,
replicarea i transcrierea ADN. Topoizomeraza II
este inta antraciclinelor, care se leag de enzim
i stabilizeaz intermediarul topoizomeraza IIADN. O cretere a expresiei topoizomerazei II este
nsoit de creterea sensibilitii la antracicline.
S-a raportat existena unei legturi ntre expresia
ARNm a topoizomerazei II i rspunsul la
antracicline (6). Gena pentru topoizomeraza II poate
fi amplificat n tumorile mamare primitive (22).
Sistemul topoizomeraza II genereaz un alt model
de rezisten multimedicament, numit impropriu
rezisten pleiotropic atipic sau MDR atipic, ceea
ce creeaz confuzii cu sistemul Pgp-170, n care
mutaiile pot afecta rezistena la MDR. Rezistena
tip AT-II (antitopoizomeraza II) intereseaz
agenii intercalani: antraciclinele, antracendiona
(mitoxantron), acridine (mAMSA), dactinomicina i
neintercalani- VP 16 (23). Exist studii care coreleaz
modificrile calitative cu apariia unei rezistene
selective la intercalani. Scderea fiziologic a
nivelului Topo II n celulele care nu sunt n diviziune
explic rezistena relativ la AT-II a unor tumori
solide care conin o fracie important de celule
n G0. Activitatea topoizomerazei II este afectat

de mai multe citostatice i determin o prim
alterare a funciei ADN prin rupturile intercatenare
i dublucatenare. Numeroase citostice stabilizeaz
cuplul ADN-enzima care blocheaz n al II-lea timp
realipirea lanurilor ADN, iniial clivate. Complexele
citostatic-enzim-ADN sunt reversibile, permind
eliberarea citostaticului.
3. Detoxifiere prin activarea sistemelor de
detoxifiere - respectiv citocromul p450 - cu
funcie mixt de oxidaz, prin creterea nivelurilor
moleculelor sulfhidril (glutationul - GSH i
metalotioninele) i a enzimelor corelate.
Glutationul (GSH) i metalotioninele par a juca un
rol major n rezistena la cisplatin i agenii alkilani.
Acestea pot lega medicamentele n citoplasm
sau nucleu, prevenind astfel interaciunea lor
cu ADN sau prevenind ADN crosslink-area.
Totui, mecanismul prin care moleculele sulfhidril
influeneaz citotoxicitatea nu este elucidat.
Glutationul - nivelul glutationului pare a fi
important n rezistena la citostatice. n unele studii
s-au detectat niveluri crescute de GSH n liniile
celulare ovariene selectate pentru rezisten la
cisplatin in vitro. Depleia GSH prin privare nutritiv
sau pretratament cu aminoacidul sintetic butionin
sulfoximin (BSO) - un inhibitor ireversibil al GSH
(synthesis enzyme gamma glutamylcysteine
synthetase) - crete in vitro citotoxicitatea la
cisplatin, melfalan i iradiere, mai ales n cazul
liniilor celulare umane de cancer ovarian (24).
Metalotioninele sunt proteine mici bogate n thiol,
care aparent particip la detoxifierea metalelor
grele. S-a observat o slab corelare ntre expresia
ARN-ului mesager al metalotioninei II i rezistena
la cisplatin n cteva linii celulare umane de cancer
ovarian. Transfecia genei metalotioninelor n
celule murine cu cancer ovarian confer rezisten
la anumii ageni alkilani. Metalotioninele pot
contribui la rezistena la agenii alkilani i iradiere.
Expresia metalotioninelor poate fi corelat astfel
cu prognosticul n cancerul mamar (25).
Modificri ale metabolismului citostaticelor:
Activarea intracelular este necesar n cazul
unor antimetabolii (rezistena la antipurinice i
antipirimidinice fiind mediate prin niveluri reduse
ale kinazelor fosforiboziltransferazelor) i ale unor
alkilani (ex. ciclofosfamid). Rezistena poate s
apar prin inactivarea expresiv (ex. dezaminarea
antimetaboliilor) sau alterarea unor cofactori (ex.
5-10 mTHF care crete inhibiia timidilat-sintetazei
de ctre FdUMP). De exemplu 5-fluorouracilul este
convertit de ctre celul la compuii fosforilai
5-FdUMP i 5-FTP. FdUMP se leag de timidilat
sintetaza, rate limiting enzyme n sinteza timidin
trifosfatului i replicarea ADN este inhibat.
Astfel, expresia timidilat sintetazei poate modula
sensibilitatea la 5-fluorouracil. Este discutabil dac
amplificarea genelor pentru dihidrofolat reductaz
i timidilat sintetaz reprezint un mecanism de
rezisten, aa cum a fost experimentat pe linii

celulare tumorale animale. Pn acum, majoritatea
studiilor pe celule tumorale umane a indicat faptul
c expresia crescut poate fi un factor de rezisten,
dar nu este sinonim cu amplificarea genic.
4. Evitarea morii celulare: Blocarea/supresia
semnalelor apoptozei (26)
Rezistena la apoptoz reprezint cea mai
puternic form de rezisten la chimioterapie.
Apoptoza este reglat de protooncogene i gene
supresoare tumorale (27). Poate fi crescut de C-myc
i sczut de Bcl2 i este reglat inclusiv de gena
supresoare tumoral p53. Proteina supresoare
tumoral p53 joac un rol central n reglarea ciclului
celular i moartea celular. Gena care codific p53,
TP53, este cel mai frecvent mutant n cancerele
mamare, circa 50% din toate tumorile fiind
estimate a fi purttoare de mutaie. n tumorile p53
wild-type, activitatea lui p53 poate fi compromis
de inactivarea activitii regulatorilor pozitivi ai
p53, precum p14 sau supraactivarea regulatorilor
negativi ai activitii p53 precum Akt (28, 29). Lezarea
ADN-ului rezult n activarea kinazelor upstream
precum ATM (ataxia-telangiectazia mutated), ATR
(ATM i Rad-3 legate) i ADN-PK (protein-kinaza
ADN dependent), care pot activa direct sau
indirect p53. Studii pe linii celulare au evideniat
experimental c alterarea funciei p53 rezult n
creterea rezistenei la diferii ageni care lezeaz
ADN (30, 31). ntr-un sumar al 11 studii care au inclus
603 pacieni cu cancer mamar, 143 (24%) au
prezentat alterarea genei p53 (32). Produsul genei
mdm-2 inactiveaz p53. Amplificarea sau expresia
alterat a acestei gene poate fi un mecanism
adiional prin care p53 este inactivat. Proteina
care iniiaz direct apoptoza este numit Bax, iar
proteina codificat de bcl-2 i exercit efectele
antiapoptotice prin formarea unor heterodimeri cu
proteina Bax. Bcl-2 confer rezisten la citostatice.
Cnd apoptoza este blocat, nici un citostatic sau
asociaie de citostatice, indiferent de doz, nu
pot determina eradicarea complet a celulelor
maligne. Supraexpresia proteinelor Bcl-2, Bcl-Xl
poate fi o alt modalitate de suprimare a apoptozei
i de ctigare a unui fenotip celular cu rezisten
la agenii care lezeaz ADN. O alt modalitate
de influenare a apoptozei este prin intermediul
cii proteinkinazei activate de stres (SAPK). Ca
rspuns la tratamentele citostatice/genotoxice,
se declaneaz o cascad intracitoplasmatic
de transducie a semnalului n care intervine
MAPK (mitogen-activated protein kinase) i ERK
(extracellular stimulus regulated kinase). Din
aceast categorie de kinaze face parte i SAPC
(stress activated protein kinase), numit i JNK
(c-jun N terminal protein kinase). Activarea SAPK
este necesar pentru moartea celular n cazul
unor categorii de stres celular, aa cum este i
chimioterapia. Inhibarea activrii SAPK are rol
protector asupra celulelor tumorale chimiotratate
June 2014
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Figura 2. Interaciunile ntre cile de transmitere a semnalelor pro-apoptotice i pro-supravieuire pot

juca un rol important n determinarea rspunsului la chimioterapie (6)
cu antracicline sau etoposid. Mecanismul exact al

implicrii SAPK este necunoscut (33). Coexpresia p53 i
PGP este frecvent asociat cu prognostic nefavorabil
(34, 35)
n cancerul mamar (figura 2).
Apoptoza este controlat prin calea extrinsec
care implic receptori ai unei superfamilii TNF, i
calea intrinsec, care implic mitocondriile i este
controlat de proteine care aparin Bcl2. Aceste
dou ci duc la activarea v-caspazelor (proteaze
care conin cistein) responsabile de expunerea
fosfatidil-serinei la suprafaa membranei celulare,
ncetarea diviziunii i fragmentarea nucleului i
citoscheletului cu formarea de corpi apoptotici.
Calea intrinsec este activat ca rspuns la lezarea
ADN-ului. n mod normal, proteinele proapoptotice
sunt eliberate din mitocondrie pentru activarea
caspazelor i iniierea apoptozei. Marea familie a
proteinelor aparinnd Bcl2 joac un rol major n
reglarea apoptozei, prin reglarea permeabilitii
96
membranei mitocondriale cu ajutorul modulrii

anumitor caspaze, n special caspaza 9, care mpiedic
eliberarea de ctre mitocondrie a citocromului C. Bcl 2 i
BclXL inhib formarea complexelor APAF1/citocrom C/
caspaza9necesare apoptozei.Mitocondriile joac un
rol-cheie n reglarea apoptozei.
ntr-adevr, n faza efectoare a apoptozei se deschid
porii de tranziie ai permeabilitii mitocondriilor.
Aceti pori sunt canale oligoproteice constituite la
nivelul membranei externe de ctre VDAC (Voltage
Dependent Anion Channel), iar la nivelul membranei
interne, de ctre ANT (Adenine Nuclotide Trans
locator). n urma deschiderii acestor pori, se
elibereaz molecule pro-apoptice, ca citocrom C,
caspazele 2, 3 i 9, precum i factorul de inducere
a apoptozei (AIF - Apoptosis Inducing Factor). AIF
este una din moleculele proapoptotice eliberate de
mitocondriile localizate n spaiul dintre membranele
mitocondriale. Proteinele AIF, citocromul C, anumite
caspaze, endonucleza G i ali factori sunt eliberai n

citosol, iniiind faza de degradare celular.
Calea extrinsec: mecanismul de activare a
receptorului Fas - Apoptosis Stimulating Fragment
(cunoscut i ca Apo1 sau CD95), joac un rol
esenial n apoptoz. Semnalele emise de Fas
recruteaz un complex format din FADD (molecula
adaptoare - Fas Associated Death Domain) i
din procaspaza 8. Formarea acestui complex
antreneaz clivajul caspazei 8 produs sub forma
sa activ dimeric, precum i cascada de activare
secvenial a diverselor caspaze, printre care i
caspaza 3. Exista dou ci de transducie a semnalelor
Fas, depinznd de tipul celulei: n celulele de tip I
(timocite), caspaza 8 activeaz direct caspaza 3, n
celulele de tip II (hepatocite), caspaza activeaza Bid
- o protein proapoptotic (BH3 interacting domanin
death agonist), provocnd eliberarea citocromului
C. Asocierea dintre citocromul C i APAF1 (Apoptotic

Peptidase Activating Factor) activeaz caspaza 9, care la
rndul ei activeaz caspaza 3.
n concluzie, rezistena la chimioterapie este o problem
major n oncologie i mecanismele de la baza ei sunt
multifactoriale (36). Nu este cunoscut care mecanism de
rezisten este dominant la un anumit pacient. Potenialele
beneficii clinice ale mecanismului de reversie a rezistenei
la chimioterapie sunt enorme. Rezistena apare nu doar la
chimioterapia tradiional, dar i la terapia intit, precum
tamoxifenul, care intete receptorul de estrogen n
cancerul mamar (37), imatinibul, care intete activitatea kinazic
a BCR-ABL translocat n CML(38) sau gefitinib, care inhib EGFR
kinaza(36,39).Fr ndoial, vor mai fi descoperite mecanisme
de rezisten pe msur ce apar medicamente noi i
descoperim noi inte terapeutice.
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June 2014
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Risk of Non Melanoma Skin Cancer in psoriasis patients with biologic therapy (up to date)
Risk of Non Melanoma Skin Cancer in psoriasis

patients with biologic therapy (up to date)
Riscul de non-melanoma skin cancer asociat
terapiei biologice din psoriasis (up to date)
Ana Livia Duta1, Cristina Medeleanu1, Cristiana Voicu1, Madalina Maftei1, Victor Gabriel Clatici2*
1. Dermatology Clinic, Elias Emergency University Hospital, Bucharest, Romania
2. University of Medicine and Pharmacy ,,Carol Davila, Bucharest, Romania
Corresponding Author: Victor Gabriel Cltici
Dermatology Clinic, Elias Emergency University Hospital, 17 bd. Marasti Street, Sector 1, Bucharest, Romania
Tel.: 0213.161.600190.224 Fax: 0213.173.052
E-mail: claticiv@yahoo.com
Open Access Article
Abstract
Keywords:
non-melanoma skin
cancer, basal cell
carcinoma, squamous
cell carcinoma, psoriasis,
biologic therapy,
prevention
Received:
16 April 2014
Accepted:
10 June 2014
Rezumat
Cuvinte-cheie:
non-melanoma skin
cancer, carcinom
Cite this article:
bazocelular, carcinom
Duta AL, Medeleanu C,
spinocelular, psoriazis,
Voicu C, Maftei M, Clatici
VG. Risk of Non Melanoma terapie biologic,
prevenie
Skin Cancer in psoriasis
patients with biologic
therapy (up to date). Rom
J Oncol Hematol. 2014;
2(2):98-102.
98
Biologic therapy represented an important step in the treatment of

immune-mediated diseases and patients with moderate or severe
psoriasis may benefit from this. In general, biologic agents are well
tolerated, with mild side effects, but the immunosuppression they
cause may favor the occurrence of malignancies, with an increased
incidence of non-melanoma skin cancer (NMSC). However, data are
confronted with the concomitant or previous use of other therapies
with increased risk of NMSC. Since it is a very common and easily
diagnosed malignancy in its early stages, the management of NMSC in
patients treated with biologic therapy consists mainly in prevention and
continuous monitoring. A diagnosed NMSC does not require treatment
discontinuation and excision is indicated, although the therapeutic
decision should be primarily based on the relative risk/benefit ratio.
Terapia biologic a reprezentat un pas important pentru tratamentul

afeciunilor mediate imun, iar pacienii cu psoriazis moderat sau sever pot
beneficia de aceasta. n general, agenii biologici utilizai sunt bine tolerai,
cu reacii adverse uoare, dar imunosupresia cauzat poate favoriza apariia
neoplaziilor, observndu-se o inciden crescut a non-melanoma skin cancer (NMSC). Datele din literatura de specialitate sunt ns confruntate de utilizarea, concomitent sau n trecut, a altor terapii cu risc pentru NMSC. Avnd
n vedere faptul c este o neoplazie foarte frecvent i uor diagnosticabil n
stadii incipiente, managementul NMSC la pacienii aflai sub terapie biologic
este n mare parte unul preventiv i de monitorizare continu. Un NMSC diagnosticat nu impune ntreruperea tratamentului i are indicaie de excizie,
dar decizia terapeutic trebuie s se bazeze n principal pe relevana utilitii
beneficiului n detrimentul riscului.
Duta AL, Medeleanu C, Voicu C, Maftei M, Clatici VG
Introducere
Tratamentul psoriazisului
Psoriazisul este o afeciune cutanat cronic,

mediat imun, caracterizat prin hiperproliferare
i turnover epidermic modificat, ceea ce duce la
un proces de cheratinizare defectuos (1). Studii
observaionale estimeaz c psoriazisul afecteaz
ntre 1% i 3% din populaie (2,3). n SUA, n cadrul
unui studiu efectuat din 2009 pn n 2010 au
fost diagnosticai 7,4 milioane de aduli, cu o
prevalen de 3,2%, care a rmas ns stabil
de la jumtatea anilor 2000 (4). Avnd n vedere
faptul c pacienii se confrunt cu o boal
cronic, manifestat prin prezena unor plci
eritematoase acoperite de scuame groase, este
inevitabil apariia implicaiilor psihosociale i
se vorbete din ce n ce mai des despre calitatea
vieii mult diminuat (5,6). Dizabilitatea este
comparabil cu cea a pacienilor cu diverse alte
boli cronice, precum afeciuni cardiovasculare,
diabet zaharat, cancer sau depresie (5,7).
Tratamentul psoriazisului folosete n principal

ageni antiinflamatori i antiproliferativi, iar
alegerea schemei de tratament depinde de multipli
factori. Forma de psoriazis, severitatea afeciunii,
dorina pacientului, comorbiditile sau tolerana
la medicamente sunt factori care trebuie luai
n considerare, iar pentru simplificarea deciziei,
American Academy of Dermatology ne propune un
ghid (22). Astfel, pentru psoriazisul n form limitat
se recomand tratament topic sau fototerapie,
iar pentru formele extinse sau non-responsive,
UVB, PUVA (psoralen-UVA), tratament sistemic sau
terapie biologic. Terapiile disponibile n prezent
includ corticosteroizi topici, analogi de vitamin D3,
fototerapie UVB i PUVA, metotrexat, ciclosporin,
retinoizi (acitretin) i ageni biologici (23).
Factorii predispozani ai psoriazisului

Exist multipli factori de risc incriminai n
dezvoltarea i agravarea leziunilor de psoriazis.
Predispoziia genetic are un rol important,
fiind descris asocierea cu alelele HLA-CW6
(PSORS1), dar i cu multe alte locusuri genetice
(8-10)
, iar acest aspect este puternic susinut
i de istoricul familial pozitiv, mai ales la
rudele de gradul I (11). Fumatul este asociat cu
severitatea clinic i crete nivelul de IL 17 i
IL 22, interleukine care intervin n exacerbarea
leziunilor (12). S-a observat c obezitatea apare de
obicei dup debutul psoriazisului i c nu exist
o cauzalitate unidirecional, ci probabil ambele
deriv dintr-o fiziopatologie comun (11,13). Un
studiu prospectiv indic faptul c obezitatea
i adipozitatea abdominal sunt factori de risc
semnificativi pentru femei, astfel nct scderea
n greutate ar putea fi o int pentru prevenia i
managementul psoriazisului (14).
Traumatismul este considerat un trigger
local, evideniat prin fenomenul Koebner, i
se manifest prin exacerbarea leziunilor dup
stimuli traumatici (fizici, chimici, electrici, chirur
gicali, infecioi) (15). Stresul psihogen este asociat
cu debutul bolii i, de asemenea, cu agravarea
leziunilor preexistente, care apar frecvent la
un interval de sptmni sau luni de zile (11,16).
Infeciile, i mai ales infeciile recente de ci
respiratorii superioare, pot declana apariia
psoriazisului, notndu-se relaia important dintre
infecia streptococic i psoriazisul gutat (17,18).
Multiple medicamente sunt incriminate ca factori
agravani, iar n managementul comorbiditilor
asociate ar trebui evitate n principal anumite
antibiotice, antimalaricele, beta-blocantele, litiul,
inhibitorii de enzim de conversie i preparatele
antiinflamatorii nesteroidiene (19-21).
Terapia biologic utilizat n psoriazis

Exist dovezi certe c psoriazisul este o afeciune
mediat imun i c limfocitele T, n principal Th1 i
Th17, au un rol important prin citokinele pe care le
secret (TNF alfa, IFN alfa) (24,25). Terapia biologic
a revoluionat tratamentul psoriazisului i const
practic n utilizarea unor ageni care acioneaz
la nivel genetic sau la nivelul procesului imun
care st la baza fiziopatologiei unei boli. Exist
patru ageni biologici disponibili, adalimumab,
infliximab, etanercept i ustekinumab, aprobai
pentru tratamentul psoriazisului n SUA, Uniunea
European i alte regiuni ale lumii (22,26-29). n
Romnia, ncepnd cu anul 2008, pacienii cu
psoriazis moderat sau sever pot beneficia de
acetia prin intermediul Programului naional
pentru tratamentul pacienilor cu psoriazis vulgar
de severitate medie i grav.
Infliximabul este un anticorp monoclonal himeric
(murinic i uman), primul din clasa anti-TNF alfa folosit
n practica medical. Mecanismul de aciune const n
legarea de molecula solubil de TNF alfa din plasm,
dar i de receptorii TNF de la nivelul membranei
celulare, blocnd astfel efectul acestei citokine.
Adalimumabul este un anticorp monoclonal uman
cu acelai mecanism de aciune ca i infliximabul i
se administreaz n injecii subcutanate, fiind foarte
eficace i n artrita psoriazic (30).
Etanerceptul este o protein de fuziune care se
leag de subunitatea Fc a receptorului TNF, avnd ca
scop final neutralizarea efectului TNF de vasodilataie,
activare a keratinocitelor i a migrrii leucocitare.
Eficacitatea i sigurana acestor trei antagoniti
ai TNF utilizai pentru tratamentul psoriazisului
moderat i sever au fost evideniate n studii
randomizate (31-34). Evidenele arat c infliximabul
ar fi cel mai eficace, adalimumabul ar avea eficien
intermediar, iar etanerceptul ar avea cea mai
slab eficacitate (35).
Ustekinumabul este un anticorp uman mono
clonal care se leag de subunitatea p40 a IL12 i
June 2014
99
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IL23, blocnd astfel aciunea acestor interleukine

i, la rndul lui, i-a demonstrat eficacitatea
att pe termen scurt, ct i pe termen lung (36).
O metaanaliz din ianuarie 2014 susine ca
infliximabul i ustekinumabul sunt cele mai eficace,
n schimb, adalimumabul prezint cel mai bun
raport cost/eficacitate, urmat de ustekinumab i
infliximab (37).
Efecte adverse ale terapiei biologice

Terapia cu ageni anti-TNF reprezint un
pas important n tratamentul psoriazisului, dar
manipularea acestei citokine poate avea consecine
negative pentru pacient, care impun ntreruperea
tratamentului. n general este bine tolerat, cu reacii
adverse uoare i limitate, care permit continuarea
tratamentului (38). Cel mai frecvent, pacienii acuz
cefalee, infecii de ci respiratorii, sinuzit, celulit
sau reacie acut la perfuzie, manifestat prin prurit
i urticarie n timpul perfuziei sau n urmtoarele
dou ore de la finalizarea acesteia (32,34,39,40).
Complicaiile infecioase au fost evideniate iniial
pe studii cu animale, ducnd chiar la reactivarea
tuberculozei latente (41,42). Astfel, pacienii cu
risc crescut de tuberculoz sau cu tuberculoz
latent trebuie s primeasc tratament profilactic
nainte de nceperea terapiei biologice i toi
bolnavii trebuie atent monitorizai pe parcursul
tratamentului (38). S-au raportat i cazuri rare de
infecii oportuniste, infecii granulomatoase la
pacienii tratai cu infliximab i etanercept, printre
care histoplasmoza, listerioza i altele (43).
Paradoxal, tratamentul anti-TNF poate fi implicat
n apariia de novo a psoriazisului, iar acest fenomen
a fost raportat pentru infliximab i adalimumab (44).
Infliximabul se folosete cu precauie la bolnavii
cu insuficien cardiac, dat fiind faptul c, folosit
n doze de 10 mg/kg, se asociaz cu agravarea
insuficienei cardiace congestive i cu mortalitate
(45)
. Un studiu realizat n 2008 a observat c pacienii
au dezvoltat Ac anti-ADN ds, cel mai frecvent de
tip IgM, n 10-12% din cazuri la adalimumab, 15%
la etanercept i 20% la infliximab i c DILE (druginduced lupus erythematosus) ar putea fi mai
degrab un efect de clas (46). Foarte rar, agenii
anti-TNF pot declana afeciuni demielinizante sau
limfoproliferative (47,48).
Un studiu recent arat c reaciile adverse
cutanate sunt strns corelate cu sexul feminin, cu
folosirea infliximabului sau a terapiei concomitente
cu corticosteroizi, iar dintre acestea, psoriazisul i
herpesul zoster sunt cel mai frecvent ntlnite (49). Se
consider c ustekinumabul este un factor de risc
pentru dezvoltarea de herpes zoster i se recomand
vaccinarea nainte de iniierea tratamentului (50,51).
TNF joac un rol important n controlul ma
lignitilor, iar blocarea efectului su prin terapia
biologic se coreleaz cu risc crescut de neoplazii
(52)
. O metaanaliz realizat n 2011 a analizat 74 de
100
studii randomizate n care s-au folosit ageni antiTNF pentru cel puin 4 sptmni i a concluzionat
c riscul relativ al neoplaziilor este de 0,99,
dar crete la 2,02 dup analiza incidenei nonmelanoma skin cancer (NMSC) (53).
Non-melanoma skin cancer (NMSC)

NMSC, incluznd carcinomul bazocelular
(BCC) i carcinomul spinocelular (SCC), este cea
mai frecvent form de cancer n medicin (54,
55)
i reprezint aproximativ 95% din patologia
oncologic cutanat (56). Incidena NMSC este de
dou ori mai mare la brbai, crete substanial cu
vrsta i crete anual la nivel global cu un procent
de pn la 8%, (57) existnd o preponderen mai
mare a BCC fa de SCC (58).
Zonele fotoexpuse sunt cele mai predispuse,
fiind cert implicarea expunerii la soare sau la surse
artificiale de radiaii UV, iar subierea stratului de ozon
accentueaz efectul nefavorabil prin creterea nivelul de
UVB de-a lungul anului (59). Fototipul deschis, folosirea
preparatelor fotosensibilizante (60), factorii ocupaionali
(61, 62)
, i expunerea la arsenic (63) sunt, de asemenea, strns
corelate cu apariia BCC i SCC i, n plus, pentru SCC,
un rol activ l joac fumatul, att prin efectul toxic, ct i
prin efectul termic (64). Imunosupresia de diverse cauze,
infecia cu virusul HPV (65,66), infecia HIV (67), limfomul de
tip non-Hodgkin (66) sau imunosupresia iatrogen (69-72)
contribuie toate la dezvoltarea NMSC.
Terapia biologic i riscul NMSC

Imunosupresia sub anti-TNF determin variaii
ale prevalenei NMSC de la 0,3 la 1,4% (73). n teorie,
terapia biologic crete riscul de malignitate prin
alterarea controlului imunitar, dar datele sunt
confruntate de folosirea concomitent sau n trecut
a tiopurinelor i a fototerapiei (74). n plus, pacienii
cu psoriazis prezint diverse comorbiditi i pot
fi tratai n acelai timp cu imunosupresoare i alte
terapii care cresc riscul de NMSC (35).
Un studiu realizat n anul 2006 asupra
infliximabului i adalimumabului la pacienii cu
artrit reumatoid a evideniat faptul c terapia
cu anti-TNF este asociat cu un risc semnificativ
de NMSC i alte tipuri de maligniti (74). Cu toate
acestea, o alt metaanaliz din 2009 a concluzionat
c folosirea acestora, n dozele aprobate, nu se
asociaz cu risc crescut de NMSC i c datele
difer prin excluderea rezultatelor unor studii mai
vechi, realizate pentru doze inadecvate (75). Recent
s-a observat c utilizarea agenilor biologici pe o
perioad scurt (< 90 zile) sau persistent (> 365
zile) n monoterapie dubleaz riscul de NMSC (76).
Folosirea ustekinumabului pentru tratamentul
psoriazisului relev un profil de siguran mai bun
n ceea ce privete dezvoltarea NMSC, incidena
fiind similar cu cea din populaia general (50,77). n
ciuda datelor obinute n urma unor trei mari studii
randomizate (PHOENIX I (29), PHOENIX II (78), ACCEPT (79)),
Duta AL, Medeleanu C, Voicu C, Maftei M, Clatici VG
au fost recent raportate dou cazuri de SCC multifocal

la pacienii expui la ustekinumab, acest lucru indicnd
totui necesitatea controalelor de rutin (77).
Concluzii
Managementul NMSC la pacienii aflai sub
terapie biologic este n mare parte unul preventiv
i de monitorizare continu. Prevenia primar
const n aplicarea unor msuri de combatere
a factorilor de risc, iar pacienii ar trebui s fie
consultai de rutin i s fie consiliai privind
msurile de fotoprotecie. Comportamentul
individual de fotoprotecie, aplicat corect nc din
copilrie, este cea mai important modalitate de
prevenie i poate scdea incidena cancerului de
piele cu pn la 80% (80-82), iar utilizarea regulat
a cremelor fotoprotectoare i-a demonstrat
eficacitatea n prevenia NMSC invazive (83).
Cancerul de piele este uor diagnosticabil
n stadiu incipient i se recomand screeningul pacienilor pentru stabilirea diagnosticului
precoce, ca prevenie secundar, innd seama de
istoricul de neoplazie, deoarece acetia sunt mult
mai expui la NMSC. Un NMSC diagnosticat are

indicaie de excizie, iar ntreruperea tratamentului
biologic nu se indic de rutin (84). Ca ultim etap,
prevenia teriar const n monitorizarea regulat
a pacienilor diagnosticai cu NMSC, prin consult
dermatologic al ntregii suprafee corporale.
ansele de a dezvolta aceste efecte adverse
sunt mult mai mici, comparativ cu rata de succes la
tratament, astfel nct sunt necesare decizii raionale
n ceea ce privete prescrierea agentului biologic n
psoriazis. Decizia trebuie s fie bazat n principal
pe relevana utilitii beneficiului n detrimentul
riscului, lucru care trebuie individualizat pentru
fiecare persoan n parte (35). Toi pacienii trebuie
s fie consiliai cu privire la riscurile acestei terapii
i, deopotriv, la eficacitatea de care muli alii
beneficiaz. Cancerele de piele reprezint cea mai
frecvent form de cancer n medicin (55), aadar,
un pacient care sub terapie biologic ar avea un
beneficiu minor, dar risc crescut de a dezvolta diverse
neoplazii, nu reprezint un bun candidat.
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103
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subjects to be part 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 as well as his/hers
phone and fax number (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/
hers complete physical and e-mail address as well

as his/hers phone and fax number. 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 and consensus declarations the abstract
will contain a general description of the article contents.
Letters to the editor and Perspective articles must not
be accompanied by an abstract.
For each article (including perspectives) the authors
must mention 3-5 keywords 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.
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 subsections.
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 the 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
System Communications.
- declare that there has been no ghostwriting (there
are no other authors except the ones mentioned
here).
The article will be publically available under
a CC BY-NC license (Licensees may copy,
distribute, display and perform the work and
make derivative works based on it only if they
give the author or licensor the credits in the
manner specified by these; Licensees may
copy, distribute, display, and perform the work
and make derivative works based on it only for
noncommercial purposes).
9. Scientific misconduct
Scientific misconduct is the violation of the standard
codes of scholarly conduct and ethical behavior in
professional scientific research. In accordance with
the COPE definition, scientific misconduct can also
be defined as:
- Intention or gross negligence leading to
fabrication of the scientific message or a false credit
or emphasis given to a scientist (Danish definition);
- Intentional distortion of the research process by
fabrication of data, text, hypothesis, or methods from
another researchers manuscript form or publication;
or distortion of the research process in other ways
(Swedish definition).
The journal and its editors will retract a publication
if there is clear evidence that the findings are
unreliable, either as a result of misconduct (e.g. data
fabrication) or honest error (e.g. miscalculation or
experimental error). Retraction is also appropriate
in cases of redundant publication, plagiarism and
unethical research.
The journal and its editors will issue an expression
of concern if they receive inconclusive evidence of
research or publication misconduct by the authors,
there is evidence that the findings are unreliable
but the authors institution will not investigate the
case, they believe that an investigation into alleged
misconduct related to the publication either has
not been, or would not be, fair and impartial or
conclusive, or an investigation is underway but a
judgment will not be available for a considerable
time.
The journal and its editors issue a correction if a
small portion of an otherwise reliable publication
proves to be misleading (especially because of
honest error), or the author / contributor list is
incorrect (i.e. a deserving author has been omitted
or somebody who does not meet authorship criteria
has been included).
For any other forms of scientific misconduct not
specified here, the journal and its editors will follow
the COPE and the ICMJE rules and regulations.
10. 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.
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
Cartea are 320 de pagini i o grafic excepional, desenele, figurile i imaginile vorbind de la sine.
Pentru a comanda cartea, contactai-ne la tel. 031 - 432 82 30 sau la adresa de e-mail: office@mediasyscom.ro
MEDIA SYSTEMS COMMUNICATION

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2014
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