Italian Journal
of
Gynaecology
& Obstetrics
December 2015 - Vol. 27 - N. 4 - Quarterly - ISSN 2385 - 0868
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
129
Italian Journal
of
Gynaecology
& Obstetrics
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Quarterly
Partner-Graf
Editor in Chief
Paolo Scollo, Catania
Editors
Herbert Valensise, Roma
Enrico Vizza, Roma
Editorial Board
Cervigni Mauro, Roma
Chiantera Vito, Napoli
Costa Mauro, Genova
De Stefano Cristofaro, Avellino
De Vita Davide, Salerno
La Sala Giovanni Battista, Reggio Emilia
Locci Maria Vittoria, Napoli
Marci Roberto, Roma
Monni Giovanni, Cagliari
Ragusa Antonio Franco, Milano
Sirimarco Fabio, Napoli
Trojano Vito, Bari
Viora Elsa, Torino
Editorial Staff
Roberto Zerbinati
Serena Zerbinati
Management, Administrative office
Partner-Graf Srl - Via F. Ferrucci, 73 - 59100 Prato
Tel 0574 527949 - Fax 0574 636250
E-mail: [email protected]
The Italian Journal of Gynaecology & Obstetrics is a digital magazine.
You can download it freely from
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It. J. Gynaecol. Obstet.
2015, 27: N.4
Table of contents
133
Editorial.
From sentinel node detection to lymphatic mapping in endometrial cancer
135
Spontaneous bilateral tubal pregnancy in a nulliparous woman. Laparoscopic
diagnosis and treatment
137
Attitudes and behavior among young and healthcare providers regarding
emergency contraception in Salerno
141
Sentinel lymph node mapping in endometrial cancer: a literature review and
state of the art
147
Correspondence.
Dienogest-containing Hormonal Contraceptives:
Natural Estradiol vs Ethinyl Estradiol
154
Paolo Scollo
Gloria Calagna, Claudio Rossi, Giorgio Adile, Maria Manzone, Antonino Perino, Gaspare
Cucinella.
Pasquale De Franciscis, Francesca Altamura, Rosa Oro, Nicola Colacurci.
Chiara Scelzo, Giacomo Corrado, Lodovico Patrizi, Emilio Piccione, Enrico Vizza.
Vincenzo De Leo
133
Editorial
From Sentinel node detection to lymphatic mapping in endometrial
cancer
Paolo Scollo
Sentinel node detection in endometrial cancer will be a very interesting and challenging
topic of research in the next few years particularly for those patients at intermediate risk in which
lymphoadenectomy could be an over-treatment.
The introduction of indocjanine green made the techinque easier and faster particularly for minimally
invasive surgery overcoming all the problems related to radioactive tracers.
The faster and wider diffution showed by indocjanine green towards lymphatics respect previous
tracers, makes this procedure more like a lymphatic mapping rather than just a sentinel node detection.
By the other hand, such a faster and wider diffution could be usefull to guide a systematic regional
lymphoadenectomy when needed.
Nevertheless, some aspects such as the site of tracer injection (intratumoral versus cervical), type of
tracer, single tracer or combination of tecnhiques, etc. need to be better standardized and data validated
on a large scale of patients.
It will be interesting if the emerging data of the italian esperience could be object of publication in
the Italian Journal during 2016.
Finally, 2015 has just passed and we close it with the last number of the Italian Journal as usuall and
I wish the readers an happy new year also under the behalf of the editorial staff.
.
Prof. Paolo Scollo
S.I.G.O. President
135
V
E
M
ICA
UT
E
IA
C
G
A
O
FARM INECOL
IN G
LA NATURA CHE AIUTA
ClimaMEV
IncontinenzaMEV
VenaMEV
FARMACEUTICA MEV - Strada Cassia Sud, 175 - 53100 Siena (SI)
Tel. 0577 378091/ Fax 0577 379970 - www.farmaceutica-mev.it
Spontaneous bilateral tubal pregnancy in a nulliparous woman.
Laparoscopic diagnosis and treatment
Gloria Calagna1, Claudio Rossi2, Giorgio Adile1, Maria Manzone1, Antonino Perino1, Gaspare
Cucinella1.
1
2
Department of Obstetrics and Gynaecology, University Hospital “P. Giaccone”, Palermo (Italy)
Obstetrics and Gynecology, “Villa Sofia-Cervello” Hospital, Palermo (Italy).
ABSTRACT
A 34 year-old nulliparous woman was referred to our
Department, complaining of vaginal bleeding and intermittent
lower abdominal cramping. serum level of β-hCG was 4954
IU/L. Transvaginal ultrasound examination revealed no
gestational sac in the uterine cavity and a right adnexal mass,
suggestive of ectopic pregnancy; left adnexal area appeared
regular. At laparoscopy, the presence of an ectopic pregnancy
was confirmed in the right tube; on the left side, surprisingly,
there was an intact infundibular ectopic pregnancy. Right
tuba was removed; considering the condition of nulliparous
of the patient, we decided to perform a linear salpingostomy.
Histologic exam confirmed the diagnosis of spontaneous
bilateral tubal ectopic pregnancies.
SOMMARIO
Una donna di 34 anni, nullipara, giunse alla nostra
osservazione, lamentando sanguinamento vaginale e crampi
addominali intermittenti. Il dosaggio della β-hCG risultava
4954 IU/L. L’esame ecografico transvaginale rivelava assenza
di sacco gestazionale in cavità uterina e l’immagine di una
massa annessiale destra, suggestiva di gravidanza ectopica. La
laparoscopia confermava la presenza di un gravidanza ectopica
nella tuba di destra; nel lato sinistro, sorprendentemente, si
evidenziava una seconda gravidanza ectopica infundibolare,
intatta. E’ stata effettuata una salpingectomia destra; in
considerazione della condizione di nulliparità della paziente,
abbiamo deciso di effettuare una salpingostomia lineare.
L’esame istologico ha confermato la diagnosi di gravidanza
tubarica bilaterale spontanea.
Keywords: Bilateral tubal pregnancy, ectopic pregnancy,
laparoscopy, salpingostomy
INTRODUCTION
In the absence of preceding induction of
ovulation, bilateral tubal pregnancy (BTP) is an
extremely unusual occurrence. Its frequency has
been estimated at 1/200 000 uterine pregnancies
and 1/725–1/1580 ectopic pregnancies (1) .
However, in the last decades a 3-fold increase
in the incidence of BTP as well as heterotopic
pregnancy has been observed, mainly related
to the rise of assisted reproduction techniques
(ARTs)(2,3). Preoperative diagnosis of BTP remains a
challenge. Serum β-hCG estimation is not reliable as
the values will be elevated more than that of a single
ectopic. Detection with ultrasound scan is almost
difficult and commonly failed in achieving a correct
preoperative diagnosis(4). We report a misdiagnosed
case of spontaneous BTP managed laparoscopically
Correspondence to: [email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-27
CASE REPORT
A 34 year-old nulliparous woman was referred
to our gynaecology Unit with an approximate
gestational age of 8 weeks, complaining of
vaginal bleeding and intermittent lower
abdominal cramping. She had no history of
oral contraceptives, intrauterine device (IUD)
or fertility drugs use, nor pelvic inflammatory
disease and abdominal/pelvic surgery. Her
menstrual history was not relevant. Interestingly,
both patient and her husband had a family history
of twins.
A physical examination revealed stable vital
signs (blood pressure: 100/60 mmHg; heart rate: 75
beats/minute). Abdomen was soft and non-tender
on palpation. At bimanual vaginal examination,
we noted a bulky uterus and the adnexa were
difficult to palpate; moreover, vaginal bleeding
was confirmed. Admission serum level of β-hCG
was 4954IU/L. Transvaginal ultrasound (US)
examination revealed no gestational sac in the
uterine cavity and a right inhomogeneous adnexal
137
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-27
mass, suggestive of ectopic pregnancy; nothing
abnormal was detected in the left adnexal area. A
small amount of fluid was present in the pouch of
Douglas. The presumptive diagnosis of right tubal
pregnancy was made.
After counseling with the patient with detailed
explanation of treatment options, a laparoscopy
was performed. Intra-operatively, a small amount
of bleeding was noted in the anterior and posterior
cul-de-sac. Uterus and ovaries were regular in
morphology. The right tube showed an intact
ectopic pregnancy (about 35x35 mm) in the
ampullary region; on the left side, surprisingly,
there was an intact infundibular ectopic pregnancy
(measuring 20x20 mm approximately), that was
bleeding and forming an organized haematoma
between the fimbriae (Figure 1). Patient had
spontaneous bilateral tubal pregnancies.
The right tube appeared greatly distended and,
during the phase of its surgical mobilization, the
rupture of the tubal wall, in its lower part, has
been caused. Consequently, we decided to remove
it, thinking that the the risks of conservative
management were higher than the possible
benefits
However, considering the condition of
nulliparous of the patient, we decided to perform
a linear tube salpingostomy with cautery on
the left tube, in order to preserve future fertility
(Figure 2); a small product of conception was
retrieved from the incision. No intra-operative
complications occurred.
Figure 2.
Detail of the intact left tubal pregnancy
(U: uterus; Ov: ovary; TP: tubal pregnancy).
Figure 1.
Intra-operative view of BTP.
All the specimens were sent for histologic
exam, which revealed the presence of inflamed
decidua with chorionic villi in both tubes. On day
1, a single-dose methotrexate (MTX) injection
(50 mg/m2) was given to reduce the risk of postsalpingostomy ectopic pregnancy persistence. We
monitored β-hCG level following the single-dose
scheme of MTX treatment: on the 7th day, β-hCG
declined to 294.3 UI/ml and 2 weeks after surgery,
it was negative. At 6 months, patient was fine and
β-hCG was negative.
DISCUSSION
138
Ectopic pregnancies are known to occur with
increased frequency after ARTs and, accordingly,
the rare event of BTP is generally related to the
in vitro fertilization - embryo transfer (IVF-ET)
treatment, as reported in medical literature(2,5,6).
Cases of heterotopic triplet pregnancy (BTP and
G. Calagna et al.
intrauterine pregnancy) after IVF-ET are also
described(3).
However, in many cases of BTP, no traditional
risk factors are identified and these cases are
called “primitive” or “spontaneous”(7-9). The real
mechanism to explain spontaneous BTP events
is unclear. Among the hypotheses, multiple
ovulation and trans-peritoneal migration of
trophoblastic tissue from one tube to another, are
included(10,11).
Pre-operative diagnosis of BTP is, to date, a
daunting task. Clinical presentation is generally
non-specific and unpredictable, and above all
there are no specific clinical features to distinguish
a BTP from a unilateral tubal form. Moreover,
transvaginal US hardly ever allows clear
identification of BTP; sometimes a visible tubal
pregnancy that coexists with a doubtful image
in the contralateral adnexa can arouse suspicion.
Finally, serum levels of β-hCG and progesterone
cannot distinguish BTP from a unilateral ectopic
pregnancy.
Consequently, BTP is diagnosed in the
operating room, when a second gestational
sac on the contralateral tube is noted during
direct inspection. However, a histopathological
examination is essential to obtain a definitive
diagnosis. Main diagnostic criterion of BTP,
first suggested by Fishblack in 1939(12) and then
confirmed by Norris in 1956(13), stated that the
histologic presence of chorionic villi in each tubes
should be sufficient to justify the diagnosis.
The management of bilateral tubal ectopic
pregnancies may be either surgical (salpingostomy
or salpingectomy) or medical (methotrexate
administration), and depends to a large extent
on the clinical status of the patient and the state
of the fallopian tubes at presentation. Use of
methotrexate is associated with a significant risk
of failure in the treatment of BTP(14). Therefore, a
surgical approach is currently preferred.
In the last few years, with the advancements
and diffusion of mini-invasive surgery (15),
laparoscopy has become the gold standard for
both diagnosis and treatment of this pathologic
condition. The specific technical approach to
choose depends on two main factors: 1. age of
the patient and the desire of future fertility;
2. status of the involved tubes. Performing a
review of international literature (including only
articles in English language), we identified six
papers describing laparoscopic management of
spontaneous BTP(4,16-20) (Table 1). All the include
articles reported a single case.
Table 1.
Review of the literature on laparoscopic treatment of spontaneous BTP.
Type of
surgery
Adjunctive
medical
therapy
Histology
Note
not reported
bilateral
salpingotomy
no
chorionic villi
in each tube.
previous conservative
laparoscopy for tubal
pregnancy and laparotomy for
corpus luteal hemorrhage.
966 IU/L
bilateral
salpingotomy
no
chorionic villi
in each tube.
recurrent left-side tubal
pregnancy (12 months after).
1 (25)
vaginal
bleeding, lower
abdominal
cramping
24.242 IU/L
bilateral
salpingostomy
yes
(methotrexate
50 mg/m2)
chorionic villi
in each tube.
fragments of fetal tissue
(vertebral column,
neurological structures,
liver, intestine, umbilical cord)
from LT.
Liao et al, 2009
(19)
1 (30)
vaginal spotting,
pelvic pain
686 IU/L
bilateral
salpingostomy
no
not reported
lysis of adhesions and left
fimbrioplasty was also
performed.
Mathlouthi et
al, 2012 (20)
1 (37)
vaginal
bleeding, pelvic
pain signs of
collapse
15.73 mIU/mL
salpingectomy
(LT);
salpingostomy
(RT).
no
immature
placental villi
(RT); placental
tissue (LT).
LT was ruptured; RT was
unruptured.
Li et al, 2014
(22)
1 (33)
vaginal bleeding
6993.1 IU/L
isthmus
resection (RT);
salpingostomy
(LT).
no
placental villi in
each tube.
left tubal pregnancy eight
years before treated with
methotrexate
Refrence
No. of
cases (Age)
Admission
symtoms
Idotta et al, 2001
(16)
1 (28)
no ymptoms
Sommer et al,
2002 (17)
1 (30)
painless vaginal
bleeding
Andrews et al,
2008 (18)
Note.
LT: left tube; RT: right tube.
Admission
serum level
of β-hCG
139
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-27
Most patients were nulliparous (4/6, 66.7%)
and, consequently, in most cases authors
performed a conservative surgical approach
(5/6, 83.3%). In only one case, a recurrent tubal
pregnancy occurred (12 months after conservative
treatment)(17).
In the case of substantial damage or active
bleeding of one or both tubes, salpingectomy
seems to be the most proper and safest treatment.
In young and nulliparous women, preservation
of at least one tube should be the main goal of
the treatment and, as in the present reported
case, salpingostomy should to be preferred.
Spontaneous conception after BTP surgery is
difficult; however, subsequent viable intrauterine
pregnancies after salpingostomy were described(21).
Currently, there is no defined protocol
regarding the addition of medical therapy after
a conservative surgical procedure. Some authors
reported the appearance of signs of a persistent
ectopic pregnancy after conservative laparoscopic
REFERENCES
140
1) Al-Quraan GA, Al-Taani MI, Nusair BM, El-Masri
A, Arafat MR, Khateeb MM. Spontaneous ruptured
and intact bilateral tubal ectopic pregnancy. Eastern
Mediterranean Health Journal 2007;13:967-72.
2) Aanesen A, Flam F. Bilateral tubal pregnancy
following in vitro fertilization and transfer of two
embryos. European Journal of Obstetrics & Gynecology
and Reproductive Biology 1996;64:235-6.
3) Hoopmann M, Wilhelm L, Possover M, Nawroth
F. Heterotopic triplet pregnancy with bilateral tubal
and intrauterine pregnancy after IVF. Reprod Biomed
Online. 2003;6:345-8.
4) Li W, Wang G, Lin T, Sun W. Misdiagnosis of
bilateral tubal pregnancy: a case report. Journal of
medical case reports 2014;8:342-5.
5) Lee JD, Chang SY, Chang MY, Lai YM, Soong YK.
Simultaneous bilateral tubal pregnancies after in vitro
fertilization and embryo transfer: report of a case. J
Formos Med Assoc. 1992;91:99-101.
6) Altinkaya SO, Ozat M, Pektas MK, Gungor T,
Mollamahmutoglu L. Simultaneous bilateral tubal
pregnancy after in vitro fertilization and embryo
transfer. Taiwan J Obstet Gynecol. 2008;47:338-40.
7) Ryan MT, Saldana B. Bilateral Tubal Ectopic
Pregnancy: A Tale of Caution. Academic Emergency
Medicine 2000;7:1160-3.
8) Marasinghe JP, Condous G, Amarasinghe WI.
Spontaneous bilateral tubal ectopic pregnancy. Ceylon
Med J. 2009;54:21-2.
9) Wali AS, Khan RS. Spontaneous bilateral tubal
pregnancy. J Coll Physicians Surg Pak. 2012;22:118-9.
10) Tabachnikoff RM, Dada MO, Woods RJ, et al.
Bilateral tubal pregnancy: a report of an unusual case.
J Reprod Med. 1998;43:707–9.
11) Amine BH, Haythem S. Extra-uterine twin
pregnancy: case report of spontaneous bilateral tubal
tubal surgery and the subsequent resolution of
symptoms and normalization of hCG levels after
treatment with methotrexate(18). Accordingly, we
decided to administer a single-dose MTX injection
to reduce the risk of post-salpingostomy ectopic
pregnancy persistence.
CONCLUSIONS
BTP represents an intriguing condition that
has been seldom reported in medical literature.
Surgeons should always keep in mind the
possibility of BTP, especially when patient has
one or more risk factors in her history. Failure
in the pre-operative evaluation of the adnexa
contralateral to the identified tubal pregnancy,
may give rise to a suspicion. Counseling is very
important in these cases and, consequently, the
therapeutic approach must be tailored for every
patient.
ectopic pregnancy. Pan Afr Med J. 2015;20:435.
12) Fishback HR. Bilateral simultaneous tubal
pregnancy. Am J Obstet Gynecol. 1939; 37:1035-7.
13) Norris S. Bilateral simultaneous tubal pregnancy.
Can Med Assoc J. 1953;68:379-81.
14) Xiromeritis P, Margioula-Siarkou C, Miliaras D,
Kalogiannidis I. Laparoscopic excision of coexisting
left tubal and right pseudotubal pregnancy after
conservative management of previous ectopic
pregnancy with methotrexate: an unusual clinical
entity. Case Rep Surg. 2015;2015:645826.
15) Cucinella G, Rotolo S, Calagna G, Granese R, Agrusa
A, Perino A. Laparoscopic management of interstitial
pregnancy: the “purse-string” technique. Acta Obstet
Gynecol Scand. 2012;91:996-9.
16) Idotta R, Tripodi A, Scopelliti P. Bilateral, tubal
pregnancy treated with conservative endoscopic
surgery. Clin Exp Obstet Gynecol. 2001;28:107-8.
17) Sommer EM, Reisenberger K, Bogner G, Nagele
F. Laparoscopic management of an unrecognized
spontaneous bilateral tubal pregnancy. Acta Obstet
Gynecol Scand. 2002;81:366-8.
18) Andrews J, Farrell S. Spontaneous bilateral tubal
pregnancies: a case report. J Obstet Gynaecol Can.
2008;30:51-4.
19) Liao CY, Ding DC. Laparoscopic management of
spontaneous bilateral tubal pregnancies. J Minim
Invasive Gynecol. 2009;16:247.
20) Mathlouthi N, Jellouli MA, Temime RB, Makhlouf T,
Attia L, Abdellatif C. Spontaneous and simultaneous
bilateral tubal pregnancy. La tunisie Medicale.
2012;90:582
21) Rani VRS, Puliyath G. Viable intrauterine
pregnancy after spontaneous bilateral tubal ectopics
in a multiparous woman: a case report. J Med Case
Rep. 2013;7:159.
Attitudes and behavior among young and healthcare providers regarding
emergency contraception in Salerno
Pasquale De Franciscis1, Francesca Altamura1, Rosa Oro2, Nicola Colacurci1
Department of Women, Child, and General and Specialized Surgery, Second University of Naples- Italy
School of Midwifery, Second University of Naples, Branch of Salerno-Italy
1
2
ABSTRACT
The aim of the study was to evaluate the knowledge and use
of emergency contraception (EC) among young, the attitude
of midwives towards EC, the organization and hospitality
of structures that prescribe EC in the province of Salerno.
Potential user of EC (539 young women attending university
and 309 young girls attending high school) and 70 midwives
were enrolled, sixteen public structures able to dispense EC
prescriptions were analysed. Anonymous questionnaire were
administered to assess knowledge and use of contraception
and EC of students, personal opinion on EC of midwives. Care
facilities were evaluated in terms of accessibility, efficiency
and ability to interact with users searching contraception.
Social platforms are the privileged source of information and
a large gap between the knowledge of contraception and the
use of contraception was found. A general positive attitude of
midwives towards EC was found together with the perception of
a lack of diffusion of contraception among women. The analysis
of the structures showed often the presence of a professional
specifically dedicated to the “reception phase”, although the
medical attitude proved unfriendly in 2/3 of the cases. In the
province of Salerno, a strong contrast is observed between
the misinformation of young people about contraception and
their need for answers that health public facilities are not able
to offer. Health facilities and spaces available for counselling
young people as regards both contraception and EC are lacking
and the awareness of “non objector” professionals is low. The
midwife, thanks to the great capacity for empathy, should be
the professional who welcomes the young patient looking for
information on sexuality and contraception.
SOMMARIO
Scopo di questa indagine conoscitiva è comprendere le
problematiche relative all’utilizzo della contraccezione
d’emergenza (CE), lo stato di conoscenza ed utilizzo tra le
giovani, l’atteggiamento delle ostetriche, l’organizzazione
e l’accoglienza delle strutture sanitarie deputate alla
prescrizione. Lo studio ha coinvolto le potenziali di CE
(539 studentesse universitarie e 309 di scuola superiore), 70
ostetriche, 16 strutture pubbliche. Attraverso questionari
anonimi sono stati indagati la conoscenza e l’utilizzo della
CE tra le studentesse e l’opinione personale delle ostetriche,
le strutture assistenziali sono state valutate in termini di
accessibilità, efficienza e capacità di relazione con l’utenza
in rapporto alla contraccezione. Le piattaforme sociali sono
la fonte preferenziale di informazioni per le giovani che
mostrano un gap molto ampio tra la conoscenza e l’uso reale
della contraccezione. Le ostetriche mostrano una generale
attitudine positiva verso la CE insieme alla percezione di
una scarsa diffusione tra le donne dei metodi contraccettivi.
L’analisi delle strutture ha evidenziato spesso la presenza di
una figura professionale specificamente dedicata alla “fase
di accoglienza”, ma l’atteggiamento medico si è rivelato
nel 2/3 dei casi poco disponibile. Nella provincia di Salerno
è evidente un forte contrasto tra la disinformazione delle
giovani sulla contraccezione e l’esigenza di ricercare risposte
che non ritengono fornite nelle strutture sanitarie territoriali.
In tal senso appare fondamentale l’implementazione di servizi
dedicati, come spazi- adolescenti o sportelli contraccezione, e
del personale non obiettore. L’ostetrica, per la sua naturale
inclinazione all’empatia, dovrebbe la figura professionale
specificamente dedicata all’accoglienza con la giovane paziente
alla ricerca di informazioni su sessualità e contraccezione.
Keywords: emergency contraception
INTRODUCTION
Unwanted pregnancies remain a public health
problem worldwide, despite the wide range of
contraceptive options available(1). World-wide in
2008 the cumulative unwanted pregnancy rate was
41% (83 million out of 208 million pregnancies):
20% ended in voluntary termination of pregnancy,
5% in spontaneous abortion and only 16% in term
pregnancies. These data show a trend of increase
through years: in 2012, out of 213 million of
pregnancies, 40% (85 millions) were unwanted:
among them, 50% ended in voluntary termination
of pregnancy, 13% in spontaneous abortion and
37% in term unplanned pregnancies(2). In Italy data
Correspondence to: [email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-28
from Ministry of Health showed a progressive
but slow reduction of voluntary termination
of pregnancy from 234.801 in 1982 (highest
incidence) to 107.192 in 2012, with a decrease of
3.8% compared to 2011(3). Voluntary termination of
pregnancy among teenagers, although low (3.4%
out of all surgical procedures in 2011), shows a
relative constant increase through the years(2).
Emergency contraception (EC), or post-coital
contraception, refers to methods of contraception
that can be used to prevent pregnancy in the
first few days after intercourse. It is intended
for emergency use following unprotected
intercourse, contraceptive failure or incorrect
use, such as incorrect use of condom or breakage,
rape or coerced sex. It needs to be taken as soon
141
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-28
as possible to obtain the maximum effectiveness,
and its use should be sporadic. A high percentage
of voluntary termination of pregnancy could be
avoided if EC was more widespread and available.
Now days, EC is strongly recommended to be
offered as part of their routine services within
family planning programs thorough encrypted
channels, carefully included in an informative,
educational and communicative system(4). It is
more and more recommended by international
organization to prevent unwanted pregnancies
and limit dramatic consequences on women and
couples(5).
The problem of EC is the little or even no
knowledge and also the neutral or negative
attitude of both health workers and women(6), as
shown in several studies(7-9). In this regard, the
results of some studies indicated a relationship
between using the EC with the knowledge and
awareness of health care personnel and the
women(10, 11). In this scenario, health care workers,
especially midwives, have a relevant role since
they are the first professionals with the first
contact with the woman searching contraception
and therefore are key to effective access to EC;
furthermore, midwives particularly play a
significant role in the provision of reproductive
health care to adolescents, therefore their attitudes
about the use of EC among teens may impact the
availability of emergency contraception options to
these clients.
In Italy EC is available from year 2000.
Although it is licensed for sale and recognized as
safe and effective as “contraceptive method”, its
use is still limited compared with potential. To
understand the issues related to the low use of EC,
we performed a survey in the province of Salerno
to evaluate: the state of knowledge and use of EC
among young, the attitude of midwives towards
EC, organization and hospitality of structures that
prescribe EC.
MATERIAL AND METHODS
142
We enrolled in an observational study lasting
12 moths: 848 potential user of EC (539 young
women attending university of Salerno aged 18-29
years and 309 young girls attending high school
aged 13-18 years) and 70 midwives working
in hospitals, private clinics, family counselling
clinics. Moreover, sixteen public structures able
to dispense EC prescriptions were analysed: 12
family counselling clinics (Salerno Via Vernieri,
Salerno Pastena, Nocera Inferiore, Cava dei
Tirreni, Baronissi, Pontecagnano, Faiano, Eboli,
Battipaglia, Capaccio Scalo, Sapri, Sala Consilina,
Omignano Scalo/Vallo della Lucania); 4 basic
medical services (Nocera Inferiore, San Marzano
sul Sarno, Sarno, Sant’Egidio del Monte Albino).
Students were interviewed by means of
anonymous questionnaire with 28 questions (5
about general information, 14 about knowledge
and use of contraception, 9 about knowledge and
use of EC). Questionnaires were administered
directly, on line (by means of private chat on
Facebook platform “ad amici di amici” or by
email) or through interview on informatics
platform. Midwives were interviewed by means
of anonymous questionnaire with 26 questions
(5 about general information, 8 about personal
opinion on EC, 6 about factors associated with EC,
6 about organization of health facilities where they
actually work or worked).
Care facilities were evaluated in terms of
accessibility, efficiency and ability to interact
with users searching contraception. The
following parameters were evaluated for the
“reception phase”: midwife present at time of
access (yes or not), attitude of midwife (score
from 1 to 3 according to unfriendly, friendly,
very friendly), mode of counselling (score from
1 to 3 according to unsatisfactory, satisfactory,
very satisfying); the following parameters were
evaluated for the “hospitality phase”: registration
of visit, performing clinical history, measuring
blood pressure, prescribing laboratory tests,
prescribing beta-hCG, performing gynaecological
examination, prescribing contraception, proposing
next gynaecological visit and ultrasonography
with Pap-test, payment of ticket for the visit.
RESULTS
Potential user of EC
As regards knowledge of contraceptive
methods, there were no differences between the
university students and the high school students.
The preferential sources of information for young
students were “Internet” and “peer”: 71% out of
309 surveyed high school girls confront friends,
48% look for answers in the websites, 30% consult
newspapers and magazines. As regards university
students, the preferred source of information is the
word of mouth among friends (57%), followed by
newspapers and magazines (48%), then internet
(45%). Conversely, as regards the role of school
and teachers only 26% of students attending
high school and 28% of university students
claims to have received lessons in sex education
in the classroom. It is not difficult to deduce
P. De Franciscis et al.
how this kind of behaviour does not increase
the knowledge and awareness of young people,
rather tends to create more confusion, since it
is simply an horizontal information peer Web,
without any scientific feature. It is remarkable to
note that social platforms like Facebook, blogs
and forums are the privileged places. As regards
knowledge of EC (Figure 1), 66% of high school
students and 93% of university declares to know
the real meaning (“use of pharmacological and
mechanical methods after unprotected sex”), is
aware of the administration methods (“as soon
as possible”: 96% of university and 86% of high
school students), the need for medical prescription
to buy the drugs (88% of university and 63% of
high school students), the places of prescription
(the majority believes to refer to the counselling
centre and to the hospital emergency room).
Midwives
As regards conscientious objection (Figure 2), 54%
believes that the right to conscientious objection
should not be raised against EC, even though 67%
declared conscientious objector and 66% is not
clearly favourable to EC and claims not disapprove
of its use “if done sensibly ... rarely and in case of
real need”. Beyond the personal position towards
the EC, the main problem according midwives
surveyed is the lack of diffusion of contraception
in general among women.
The picture of the situation does not differ
from reality emerged from the data of the survey
conducted on the student population. As regards
counselling about CE, 83% of midwives work in
a hospital facilities where EC is prescribes and in
which the professional dedicated to reception is
the midwife (31%), the physician (10%), midwife
and7or physician (10%), nurse and/or midwife
and/or physician (5%), not identified (51%).
“Reception phase” and “hospitality phase” are
managed by physician (39%), midwife (33%),
either from your physician or midwife or nurse
(28%). As regards the quality of EC service offered
by the structures in the Salerno area, 57% of
midwives considers that the service is improvable,
particularly as regards increasing the number of
facilities able to prescribe EC.
Figure 1
Knowledge and personal experience of emergency contraception
among potential users (university students: black square, high
school students: white square).
As regards EC personal use, there is a very
large gap between the knowledge and the actual
use of contraception. In fact, most of the surveyed
university students (84%) use condoms and
most of high school students (66%) use coitus
interruptus, only 25% of universities and 4% of
high school students use oral estroprogestin; 9%
of high school students and 27% of universities
claim to have made use of the EC. As regards
sexual experience, 70% of universities versus 46%
of high school students has a stable relationship.
No difference was found as regards age of first
sexual intercourse: 3% begins sexual activity
between 12 and 14 years old, 40% between 15 and
18, 36% between 19 and 25, 1% after 25 years old,
13% report have not yet had sexual relations after
25 years old.
Figure 2
Midwives’ opinion about emergency contraception.
Health facilities
It is worth noting that 57% of the girls
interviewed do not consider the public health
facilities the best place where they can find
answers to their needs of contraception. As regards
“Reception phase” (Table 1), the analysis of the
structures showed in 8 out of 12 cases the presence
of a professional specifically dedicated to the
“reception phase”, which is able to pay particular
attention to the psycho-emotional support and to
“listening” in the majority of cases (6 of 8).
143
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-28
The medical attitude proved unfriendly in 2/3
of the cases, mostly when the nurse was the first
professional facing with patient; only in 4 out of
12 structures a contraception counselling adequate
for time and clarity with respect to different
contraceptive options was performed. As regards
“Clinical work-up and prescription” (Table 1),
family clinics appear to show a behaviour
consistent with that provided by the guidelines.
In all of the structures an essential medical
history collection was performed, although it
was particularly thorough only in three of them.
No structure performed laboratory tests before
EC prescription, in only one case gynaecological
examination was requested. In four facilities the
drug was not prescribed because nor the GP or
the gynaecologist or doctor’s prescription was
lacking. The ticket for medical visit was never
Table 1
“Hospitality phase” of twelve counselling clinics.
physician
physician
No,
Yes
Yes
No,
nurse
Yes
3
1
3
3
3
1
1
3
1
3
3
3
Yes
Yes
Yes
Yes
Yes
Yes
Measurement of blood
pressure
Yes
No
No
No
No
Prescription of laboratory tests
No
No
No
No
Prescription of β-hCG
No
No
No
Performing gynaecological
No
No
Prescription of contraceptive
method
Yes
Prescription of laboratory tests
Midwife present
at reception
Yes
Yes
Yes
Attitude of midwives*
2
3
Mode of counselling**
1
Registration of visit,
performing clinical history
No,
No,
Yes
Yes
2
2
3
3
1
1
1
1
1
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
No
No
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
Yes
No
No
No
No
Yes
Yes
No
No
No
No
No
No
Proposal of next
gynaecological visit,
ultrasonography and pap-test
No
No
Yes
No
No
Yes
Yes
No
No
No
No
No
Payment of ticket
No
No
No
No
No
No
No
No
No
No
No
No
physician
*attitude of midwife: score from 1 to 3 according to unfriendly, friendly, very friendly
**mode of counselling (score from 1 to 3 according to unsatisfactory, satisfactory, very satisfying).
requested, a further medical consultation was
never recommended. The attitude of the basic
medical services was quite different, because the
prescription of EC was rejected by the physicians.
DISCUSSION
144
Successful use of EC requires accurate
knowledge of and favourable attitude towards
EC methods(12). Despite young present themselves
strong in their convictions and capable of living
sexuality, many of them seem to live their
sexuality in a not fully aware way: it’s clear the
a strong contrast between the use of inefficient
contraceptive methods and misinformation, on the
other part the need to look for answers that the do
not believe to be provided in health facilities across
territorial facilities. Most of the young people
P. De Franciscis et al.
surveyed do not consider the available health
facilities a reference point to their needs for sexual
and reproductive health: therefore it’s mandatory
to rethink the organization of local health services
targeted to meet the needs of such young patients
users. It’s noteworthy that the actual use of safe
contraception appears to be low compared to
deepen knowledge about contraceptive methods:
the reasons of poor use of hormonal contraception
are obviously different from the lack of knowledge,
and should be investigated if its spread should be
promoted. One would imagine a high utilization
of the EC in relation to the high failure rate of
contraceptive methods routinely used (condom,
coitus interruptus), as stated by most girls. In
this regard there is need of educational projects
and campaigns both with direct interventions
in schools and youth associations, but mostly
through dedicated websites supervised by
scientists. Our data show the need for greater
awareness of the obstetricians and physician to the
need to provide complete and comprehensive the
EC, which currently needs a better receptive and
hospitality phase. The latter is the most delicate
and cannot ignore the protection of the health of
the psycho-emotional woman, worried about the
risk of a possible unwanted pregnancy and the
related consequences, but also for the expectation
of solving the problem (i.e. prescription of EC).
Data show that health facilities manage the
reception phase in an unsatisfactory without
establishing a real relationship that puts the
woman at the centre of care. The reason is
probably the frequent lack of midwife during the
reception phase. This is all the more serious in
view of a teenager, which probably approaches
the first time to a health facility and expects a
greater capacity for empathy. In this view, it is
fundamental to implement special services such
as “space teenagers” or “points of contraception”
that could satisfy, through trained and dedicated
professionals, even in times outside of those
canonical office that clash with the routine school
activities, their legitimate expectations of response
to the questions of sexuality and contraception
The EC is a central aid of contraception,
allowing women of different age groups to fully
enjoy their life as a couple, not to feel panicked for
anxiety of having made irreparable mistakes, as a
result of a not adequately protected intercourse.
The EC also could allow to repair the point of
disconnect between voluntary termination of
pregnancy and failure of usual contraception. The
request for EC could also represent an opportunity
to encourage the woman and couple to rely on
care facilities, particularly territorial ones, without
the fear of having to be judged, for subsequent
moments of reflection that will allow to address
the issue of prevention contraceptive.
The EC is still poorly accepted by a large part
of health care professionals and the general public
who continue to consider it an abortion procedure
and opt for a controversial conscientious objection.
It’s well known that the use of the EC depends
on many factors: functioning of health facilities
devoted to the prescription, the sensitivity of health
workers, the information received from potential
users are absolutely relevant(13). Moreover, it is
proven that information campaigns targeted to
users (such as educational interventions in schools
and advertising campaigns promoted by scientific
societies), spaces dedicated to listening and
consulting in territorial medicine (such as spaces
“teenager” available in some counselling centres),
awareness of professionals (such as specific
training courses), may significantly increase the
demand for EC prescription and the compliance
to long-term contraceptive programmes.
In conclusion, the results of this research in
the province of Salerno showed among young
adequate knowledge but misuse of contraception,
a positive attitudes of health workers about the
some aspects of EC method, the lack of adequate
health facilities and spaces available for counselling
young people as regards both contraception and
EC. It feels the need for territorial medicine which
may offer both convenient times and spaces for
teenagers, and “non objector” professional willing
to listen, to education and prescription.
DECLARATION OF INTEREST
The Authors have no financial affiliation (e.g.,
employment, direct payments, stock holdings,
retainers, consultantship, patient-licensing
arrangements, or honoraria) or involvement with
any commercial organization with direct financial
interest in the subject or material discussed in this
manuscript. The Authors have no financial interest
in any aspect of the work and did not receive any
financial support. Any other potential conflict of
interest also is disclosed.
145
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2015, 27: N.4
DOI: 10.14660/2385-0868-28
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Sentinel lymph node mapping in endometrial cancer: a literature review
and state of the art
Chiara Scelzo1, Giacomo Corrado2, Lodovico Patrizi1, Emilio Piccione1, Enrico Vizza2
Department of Surgery, Section of Gynaecology and Obstetrics, Tor Vergata University, Rome, Italy.
Department of Surgical Oncology, Gynecologic Oncology Unit, “Regina Elena” National Cancer
Institute, Rome, Italy
1
2
ABSTRACT
Objective: Sentinel lymph node biopsy has proven safe and
feasible in a number of gynecologic cancers such as vulvar
cancer, cervical cancer, and endometrial cancer. The aim of
sentinel node mapping is to decrease the morbidity associated
with a complete lymphadenectomy, while also increasing the
detection rate of small lymph node metastases. The scope of
this review is to critically appraise the published literature on
(Sentinel Lymph Node) SLN procedure in endometrial cancer
(EC).
Methods: We run a PubMed search for publications in English
using “endometrial cancer” and “sentinel node” as key words.
All abstracts from 2005 to December 2015 were reviewed. We
excluded studies aimed to determine the risk of metastasis in
the remaining non-SLNs when the SLN is positive, studies that
only reported on successfully mapped patients, those where
different types of gynecological cancers other than EC and/
or atypical endometrial hyperplasia were included and those
studies with less than 30 cases.
Results: 23 studies met the inclusion criteria. The overall
detection rate of sentinel nodes after cervical injection ranged
from 62% to 100%, while it was 73% to 95% after corporeal
injection. All studies with n of cases ≥ 100 had overall
detection rates of >80%. In terms of product/tracer used,
Technetium colloid, blue dye and ICG were used either alone
or in combination. Detection rates were good for all three
products, however, detection rates were higher when blue dye
was combined with Technetium (Tc) or Indocyanine Green
(ICG). The injection site influenced the pattern of sentinel
mapping with para-aortic SLNs being found more often using
corporeal and deeper (3–4 cm) cervical injection techniques.
Studies in which the protocol included a systematic para-aortic
lymphadenectomy had higher detection of para-aortic SLNs,
as well as isolated para-aortic metastases.
Conclusion: Sentinel lymph node mapping for endometrial
cancer balances the need to assess nodal disease with the
low likelihood of nodal metastasis for most patients. It is a
technique with minimal morbidity, sparing the need for a
full lymphadenectomy and its associated higher morbidity
potentially leading to a greater utilization by gynecologic
surgeons in the future. Achieving high bilateral SLN detection
rates and low false-negative rates is mandatory to implement
the SLN mapping as a routine component of clinical practice.
Keywords: Sentinel Lymph Node Mapping, Endometrial Cancer,
Indocyanine Green
Correspondence to: [email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-29
SOMMARIO
Obiettivi: La biopsia del linfonodo sentinella si è dimostrata
sicura e fattibile in vari tipi di tumori ginecologici, come
nei tumori della vulva, della cervice e dell’endometrio.
L’obiettivo della procedura del linfonodo sentinella nel
tumore dell’endometrio è quello di diminuire la morbidità
associata con una linfadenectomia totale ed allo stesso tempo
incrementare l’individuazione di micrometastasi linfonodali.
Lo scopo di questa review è di valutare criticamente la
letteratura pubblicata sulla procedura del linfonodo sentinella
nel tumore dell’endometrio.
Metodi: Abbiamo eseguito una ricerca su PubMed per
pubblicazioni in lingua inglese utilizzando “endometrial
cancer” e “sentinel node” come parole chiave. Sono stati rivisti
tutti gli abstracts dal 2005 al Dicembre 2015. Abbiamo escluso
gli studi il cui unico obiettivo era quello di determinare il
rischio di metastasi nei rimanenti linfonodi “non-sentinella”
quando il linfonodo sentinella risultava positivo, studi che
riportavano solo pazienti in cui la procedura aveva avuto
successo, quegli studi che includevano diversi tipi di tumori
ginecologici oltre al cancro dell’endometrio e studi con un
numero di casi inferiore a 30.
Risultati: 23 studi hanno risposto ai nostri criteri di inclusione.
Il tasso d’identificazione complessivo dei linfonodi sentinella è
risultato variare tra il 62% ed il 100% dopo iniezione cervicale
e tra il 73% ed il 95% dopo iniezione nel corpo dell’utero.
Tutti gli studi con un numero di casi ≥ 100 hanno mostrato
un tasso di identificazione complessivo maggiore dell’80%.
Riguardo al tracciante/prodotto utilizzato, il Tecnezio99m (tc),
i coloranti blu ed il verde di indocianina sono stati usati da
soli o in combinazione. I tassi d’identificazione sono risultati
buoni per tutti i prodotti utilizzati, ma si sono evidenziati
risultati migliori quando il colorante blu è stato utilizzato in
combinazione con il tecnezio o con il verde di indocianina. Il
sito d‘iniezione ha influenzato la localizzazione dei linfonodi
sentinella individuati, mostrando che i linfonodi sentinella
para-aortici vengono individuati più frequentemente quando
sono utilizzate tecniche di iniezione nel corpo uterino o più
profondamente nella cervice (3-4 cm). Gli studi in cui i protocolli
prevedevano una linfoadenectomia para-aortica sistematica
hanno mostrato un tasso maggiore d’identificazione di
linfonodi sentinella para-aortici così come un tasso maggiore
di metastasi isolate dei linfonodi para-aortici.
Conclusioni: La procedura del linfonodo sentinella nel tumore
dell’endometrio consente di bilanciare la necessità di valutare
l’eventuale presenza di malattia linfonodale con la scarsa
probabilità di metastasi linfonodali nella maggior parte delle
pazienti. E’ una tecnica gravata da una minima morbidità.
Risparmiando la necessità di una linfoadenectomia totale con i
suoi maggiori rischi di morbidità e di mortalità rappresenta una
tecnica che può potenzialmente divenire nel prossimo futuro
di maggiore utilizzazione da parte dei chirurghi ginecologi. E’
mandatorio ottenere un alto tasso d’identificazione bilaterale
e bassi tassi di falsi-negativi al fine di poter includere la
procedura del linfonodo sentinella come una metodica di
routine nella pratica clinica.
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DOI: 10.14660/2385-0868-29
INTRODUCTION
148
Sentinel Lymph Node (SLN) mapping is
currently gaining popularity in gynecology
oncology. The advantage of a sentinel node biopsy
is lower morbidity than full lymphadenectomy and
the potential for improved diagnostic accuracy.
SLN biopsy has revolutionized treatment of breast
cancer and melanoma, and the accuracy results in
early stage vulvar and cervical cancers have been
very encouraging(1-5).
Endometrial cancer (EC) is the most common
gynecologic malignancy in developed countries,
with more than 54,000 new cases estimated for the
year 2015 in the United States(6). Despite this high
prevalence, management is an issue of significant
debate and controversy. Balancing complete
staging information for both prognostic and
potential therapeutic benefits against potential
perioperative morbidity and mortality has been
the aim of numerous studies to estimate the
relationship between clinical and pathologic
characteristics in endometrial cancer. Surgery
is the standard of treatment of EC. In particular,
hysterectomy (with or without salpingooophorectomy) allows to remove primary tumor
and to identify patients at high-risk of developing
recurrences. However, no consensus on the
execution of retroperitoneal staging still exists.
The American College of Obstetricians and
Gynecologists recommended the execution of
lymphadenectomy. Therefore lymph node staging
remains an important part in EC treatment(7).
Different retrospective studies evaluated the role
of lymphadenectomy suggesting the prognostic
and therapeutic role of retroperitoneal staging(8).
However, these results were not supported by the
two randomized trials comparing hysterectomy
plus lymphadenectomy versus hysterectomy
alone in the management of early stage EC(9).
In fact, they suggested that lymphadenectomy
increases morbidity without improving oncologic
outcomes. Although their study designs have
been largely criticized because of big biases,
these trials provide an overview of the lack of
consensus on EC management(9). Most patients
with endometrial cancer will present with earlystage disease. Although the rate of metastasis in
these patients is low, offering excellent prognoses,
the standard of treatment in many practices still
includes a complete or selective pelvic and paraaortic lymphadenectomy for staging; accurate
surgical staging being the most important
prognostic factor. Many patients will undergo
a comprehensive lymphadenectomy despite
having disease confined to the uterus, resulting
in prolonged operating time, additional cost, and
potential side effects, such as lower extremity
lymphedema. However, recent studies show
that a complete lymphadenectomy may have no
therapeutic benefit in patients with early-stage
endometrial cancer(10). SLN mapping, which
has been used in other cancer types, may be an
acceptable compromise between a complete
lymphadenectomy and no nodal evaluation in
patients with EC. SLN mapping is based on the
concept that lymph node metastasis is the result
of an orderly process; that is, lymph drains in
a specific pattern away from the tumor, and
therefore, if the SLN, or first node, is negative for
metastasis, then the nodes after the SLN should
also be negative. This approach can help patients
avoid the side effects associated with a complete
lymphadenectomy, although disease must be
thoroughly staged for accurate prognosis and
determination of appropriate treatment approach.
The aim of our study is to critically review the
published literature on SLN procedure in EC. We
hope to offer help refining the methodology that
should be used and applied to future studies.
MATERIALS AND METHODS
We run a PubMed search for publications in
English using “endometrial cancer” and “sentinel
node” as key words. All articles from January 2005
to December 2015 were reviewed. Full relevant
articles were assessed. We excluded studies
aimed to determine the risk of metastasis in the
remaining non-SLNs when the SLN is positive and
to identify the factors that can predict the risk of
lymph node metastases. Additionally, studies that
only reported on successfully mapped patients
and those where different types of gynecological
cancers other than EC and/or atypical endometrial
hyperplasia were excluded. We included only
studies with a minimum of 30 cases using the
same injection approach. In case of multiple
publications from the same research team, the
most recent study was selected.
Descriptive statistics were used. We considered
injection site and injection product/tracer.
Outcome measures were:
• Detection rates (defined as proportion of
patients with at least one SLN detected)
• Sensitivity: patients with positive-SLN
divided by all metastatic patients (true positive
tests/all positive patients);
• Specificity: patients with negative-SLN
divided by all non-metastatic patients (true
negative tests/all negative patients)
C. Scelzo et al.
• Negative predictive value: negative-SLN
patients who are non-metastatic divided by all
patients without a positive-SLN (true negative
tests/true negative + false negative tests);
• False negative rate: metastatic patients
without a positive-SLN divided by all metastatic
patients (false negative tests/false negative + true
positive tests);
• Unilateral versus bilateral mapping;
• Para-aortic mapping and the impact of
ultra-staging
RESULTS
We identified 108 abstracts. Review articles,
commentaries, meta-analysis or other types of
publications that did not meet our inclusion
criteria were excluded. We identified 86
retrospective/prospective studies. From these, 24
studies were excluded because they had less than
30 patients, 19 because they included patients
with atypical endometrial hyperplasia or other
gynecologic cancers, and 10 because they did not
report results on all patients that underwent SLN
procedure. 10 studies were not considered as they
were from the same research team using the same
database. In this case we only considered the most
recent study.
23 studies met our inclusion criteria (11-34).
Among these studies different injection
techniques have been used. Studies differ by
injection site and injection product. We identified
three different sites of injection; in the cervix, in
the myometrium (subserosal) and peritumoral by
hysteroscopy or by transvaginal ultrasonography.
Cervical injection could be deep or superficial
submucosal. To simplify we separated these in
two categories: cervix and corporeal injections.
Of the 23 studies reviewed, 13 used cervix as
the only injection site, 8 used a corporeal method
of injection, and 2 studies used both injection sites
in the same patient(20, 29) (Table 1). The total number
of patients in the cervical injection category was
higher than the total number in the corporeal
injection category (1437 versus 490). The overall
detection rate of sentinel nodes after cervical
injection ranged from 62% to 100%, while it was
73% to 95% after corporeal injection. All studies
with n ≥ 100 had overall detection rates of >80%.
Regarding the product/tracer used, we
identified: Technetium colloid, blue dye and
indocyanine green (ICG). These could have
been used alone or in combination. The choice
of injection product depends on both its ability
to be detected in the sentinel nodes and on its
ease of use. The injection agents identified in our
review included technetium colloid (Tc), blue
dye (methylene blue or lymphazurin), and (ICG).
Technetium colloid can be detected for a longer
period of time and therefore is often injected preoperatively. Surgeons can be guided to the mapped
regions by a pre-operative lymphoscintigram
or SPECTCT, however correlation between
imaging done the day before surgery and the
intra-operative findings is low(20, 34). It may be
more difficult to detect SLNs close to the cervix
as the gamma-probe picks up high activity from
the injection site. The resources and equipment
required for Tc mapping are cumbersome, costly,
and are not available to all surgeons.
Blue dye is a much cheaper product and is
widely available in most hospitals. It also is more
convenient to use because it is injected intraoperatively, however it may be more difficult to
detect in obese patients(35). Allergic reactions are
known to occur; but severe reactions are very
rare (0.1%)(36). ICG is a new injection agent that
relies on near-infrared imaging. This method is
expensive because it requires the use of specialized
equipment; however early reports on its use in
cervical and endometrial cancer suggest very high
SLN detection rates(35, 37, 38). Table 1 summarizes
detection rates according to injection technique.
Overall detection rates were good for all three
products. However, detection rates were higher
when blue dye was combined with Tc or ICG.
Furthermore, as the lymphatic drainage in the
pelvis is not unilateral, bilateral detection rates
are the most clinically relevant. Seventeen studies
reported on bilateral sentinel node detection rates.
It ranged from 34 to 100% for cervical injection.
There are two studies using just corporeal injection
that reported on bilateral detection having a rate
of 37 and 19%(16, 27). There may be a tendency for
higher bilateral detection with cervical injection,
and combining blue dye to Tc or ICG resulted in a
higher bilateral detection rates than blue dye alone
(Table 1).
One of the most debated aspects of the EC
staging is the extent of lymphadenectomy and
whether it should be performed in pelvic only or
in pelvic and para-aortic full dissection. It has also
been criticized that SLN mapping would translate
to a low para-aortic detection rate. It has been a
convention that uterine lymphatics drain through
the paracervical tissues, but lymphatic drainage
also occurs through the infundibolo-pelvic
ligament or via pre-sacral lymphatics directly to
the aortic bifurcation(17, 39, 40). It was observed that
the injection site influenced the pattern of sentinel
149
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-29
Table 1
Sentinel Lymph node detection rates by injection method and tracer used.
Author
(reference)
N
Tracer Used
Injection Site
Overall detection
rate (%)
Bilateral detection
rate (%)
Ballester (11)
125
Blue dye +
technetium
Cervix
89
62
Bats (15)
43
Blue dye +
technetium
Cervix
70
37
Niikuraa (13)
55
Blue dye +
technetium
Cervix
78
49
Naourac (31)
180
Blue dye +
technetium
Cervix
88
63
Robova (14)
67
Blue dye +
technetium
Corpus
73
NA
Delaloye (16)
60
Blue dye +
technetium
Corpus
82
37
Niikuraa (13)
55
Blue dye +
technetium
Corpus
78
49
How* (17)
100
Blue dye +
technetium
Cervix (deep)
92
66
Lopez-de la Manzanara
(18)
50
Blue dye +
technetium
Cervix (deep)
92
34
Muckeb (19)
31
Blue dye +
technetium
Cervix (deep)
90
52
Sawicki* (20)
70
Blue dye +
technetium
Cervix + Corpus
97
76
Barlin (12)
498
Blue dye
Cervix
81
51
Desai (21)
120
Blue dye
Cervix
86
52
Vidal (22)
66
Blue dye
Cervix
62
35
Mais (23)
34
Blue dye
Cervix
62
NA
Lopes (24)
40
Blue dye
Corpus
78
NA
Farghalli (33)
93
Blue dye
Corpus
73,1
NA
Tornè (27)
74
Technetium
Corpus
74
19
Solima (26)
59
Technetium
Corpus
95
NA
Favero (32)
42
Technetium
Corpus
73
NA
Holloway (25)
35
Blue dye + ICG
Cervix
100
100
How* (28)
100
Blue Dye or Patent
Blue + ICG + Tc
Cervix (submucosal
+ deep)
92
76
Sawicki* (29)
188
Radiocolloid +
Blue Dye or Blue
dye
Cervix+
Corpus
Cervix + Corpus
90,9
72,5
a
This study presents separate results for 2 different injection sites (cervical and corporeal) therefore we divided their results in
this table by injection site for relevance. Note: Corporeal injection: 30 patients had Technetium only; Cervical injection: 1 patient
had Technetium only.
b
Transcervical injection to isthmocervical junction, considered “deep cervical”.
c
In this study a dual cervical injection was performed: submucosal + deep.
*The two studies from How et al and the two from Sawicki et al referred to different population. Therefore they have been all
included
150
C. Scelzo et al.
mapping. Para-aortic SLNs are found more often
using corporeal and deeper (3–4 cm) cervical
injection techniques. Isolated para-aortic SLNs are
uncommon. Studies in which the protocol includes
a systematic para-aortic lymphadenectomy have a
higher rate of detecting para-aortic SLNs, as well
as isolated para-aortic metastases(24, 27).
Finally, regarding ultrastaging we observed
a broad difference of protocols among different
centers and clear guidelines for SLN ultrastaging
have not been established in gynecologic
pathology.
DISCUSSION
At present, even if recently the National
Comprehensive Cancer Network acknowledged
the use of SLN mapping for endometrial cancer as
an acceptable option for surgical treatment(41), the
role of SLN biopsy in endometrial cancer is less
clearly defined than in breast cancer, melanoma,
or early stage vulvar and cervical cancers. Optimal
timing of injection, best site of injection and the
most appropriate tracer material are still being
actively investigated. Three important features on
the role of SLNM in EC deserve to be addressed.
First, three different types of SLN mapping
techniques exist based on site injection: uterine
subserosal, cervical and endometrial via
hysteroscopy.(42, 43)
Second, in the last years different methods
have been implemented for improving delineation
of lymphatic drainage. Since 1996, blue dye with
or without technetium, has been the predominant
dye used to identify SLNs(39). Detection rates
of approximately 80 % have been reported in
literature. However, the results do not reflect
bilateral detection rates which are the most
clinically relevant as the lymphatic drainage in
the pelvis is not unilateral(44). When looking at
bilateral rates the bilateral mapping occurs in
approximately half of the cases. This means that
approximately half of the patients would still
need a form of lymphadenectomy and bilateral
detection rates need to see improvement. Near
Infrared (NIR) fluorescence with indocyanine
green (ICG) has been described for SLN mapping
in several types of cancer with promising results
in terms of detection rates, NIR imaging appears
to provide beneficial techniques for SLN mapping
in gynecologic malignancies. NIR imaging
capabilities are now available for the da Vinci SI
robotic platforms as well as for laparoscopic and
open approaches (PINPOINT and SPY Elite). Small
single series have been already published(25, 38, 45) and
ongoing studies are trying to assess the detection
rate of SLNs for gynecological cancers using ICG
and NIR fluorescent imaging(46).
Third, in many centers for SLNs enhanced
pathology assessment is performed if the initial
H&E is negative. Ultrastaging involves additional
sectioning and staining of the SLN with H&E and
immunohistochemistry (IHC) to examine the SLN
for low volume metastatic disease(47) including
micro-metastases (MMs) and isolated tumor
cells (ITCs)(48). The role of MMS and ITC has not
yet been defined and needs to be addressed. In
fact, due to the implementation of ultrastaging
during SLN mapping procedures, a growing
number of patients will be diagnosed with ITCs
and MMs in comparison with patients undergoing
conventional procedures.
Finally, as SLN mapping for EC is gaining
acceptance, a larger number of patients
will undergo SLN removal without a full
lymphadenectomy. The management of these
patients needs to be addressed and the role of a
second surgical step for patients with positive SLNs
should be studied. In patients with endometrial
cancer, techniques in SLN mapping/biopsy
continue to evolve. Advancements in surgical
treatment approach, staging, and technology
have led to decreased false-negative rates and
improved detection rates. Complete or selective
pelvic and para-aortic lymphadenectomy remains
the standard of therapy for now, as surgical
staging is the most important prognostic factor
in this group of patients; however, SLN mapping
is rapidly gaining ground. This authoritative
acknowledgment will likely influence standards of
care for women with endometrial cancer around
the world. The body of evidence for results with
this new standard will expectedly increase.
An optimal route of tracer administration
is a principal question related to the use of SLN
mapping in endometrial cancer, followed by the
choice of the tracer and the issue related to the
corrected timing of the injection.
Lymphatic mapping using SLN biopsy
through intraoperative injection of a mixture of
blue dye, ICG, and radioactive technetium into the
cervix appears to be feasible and convenient, and
provides good results in patients with endometrial
cancer. Indocyanine green is demonstrated to be
superior to blue dye and comparable to 99mTc-SC
in terms of SLN mapping. A combination of ICG
and 99mTc-SC has a high detection rate of SLN,
resulting in fewer complete lymphadenectomies
and their associated morbidity. Due to satisfactory
detection rates with ICG and 99mTc-SC, blue
151
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-29
dye may not be essential to SLN detection in
endometrial cancer. Large multi-institutional
randomized studies comparing SLN mapping to
comprehensive lymphadenectomy in endometrial
cancer will be required to confirm the excellent
negative predictive values and high sensitivity for
detection of disease.
Sentinel lymph node mapping for endometrial
cancer balances the need to assess nodal disease
with the low likelihood of nodal metastasis for
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Correspondence
It. J. Gynaecol. Obstet.
2015, 27: N.4
DOI: 10.14660/2385-0868-030
Dienogest-containing Hormonal Contraceptives:
Natural Estradiol vs Ethinyl Estradiol.
Vincenzo De Leo
Department of Molecular Medicine and Development. Section of Gynaecology and Obstetrics Policlinico “Le Scotte” Siena University- Italy
In recent years, many birth control pill brands
were placed on the market, which created, in
many cases, a lot of confusion rather than bringing
benefits, both among gynaecologists and among
women. The lower cost of generic pills and the
higher number of products has shifted the debate
from safety and efficacy to cost, as an opportunity
for increased use of oral contraceptives (OCs) by
Italian women, for whom the use of contraceptive
pills has always been the lowest in Europe.
The real debate, however, should always
remain focused on safety and the lower risks to
women’s health, so as to improve compliance
by women. Much has changed since oral
contraceptives have been placed on the market,
more than 50 years ago, with reduced dosage of
steroid hormones.
New progestins, in combination with lower
doses of Ethinyl Estradiol (EE), the predominant
estrogen component, helped reduce the incidence
of venous thromboembolism and other negative
side effects associated with the use of OCs. In
the past, some attempts have been made to
replace EE with natural Estradiol (E2), all failed
due to poor control of the menstrual cycle.
Recently, the debate has focused again on this
molecule, with the new pills containing natural
estrogens. Despite the fact that EE and OCs are
safe, there are some side effects that can affect
women, particularly women smokers. Possible
negative effects concern coagulation, myocardial
infarctions, stroke, weight gain and lack of libido.
Other possible effects include spotting, breast
tenderness, nausea, headaches and mood changes.
As already mentioned, a reduced dosage of EE
154
Correspondence to:[email protected]
Copyright 2015, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-030
has significantly reduced this risk, even though
an excessive estrogen production increases the
percentages of menstrual irregularities and,
consequently, favours the discontinuation of the
pill. Switching to natural estrogens was not easy
and, only once the E2 valerate/Dienogest was
developed in a dynamic regime, the right balance
was reached, which allowed a good control of the
menstrual cycle and the reduction of side effects
related to EE. Dienogest is certainly an important
innovation in the field of progestins, thanks to its
marked uterotrophic activity, in association with
anti-estrogenic activity, able to reduce nuclear
estrogen receptors in the endometrium, with
important effects on endometrial proliferation.
Therefore, after 4-5 years of experience with this
formulation (E2V/DNG), we can say that there is
a good control of the menstrual cycle in women
who use it. As for the antiandrogen action of
Dienogest, literature data are controversial,
although all women report an improvement in
the main hyper-androgenic symptoms, such as
acne and hirsutism. As for the metabolic impact,
and in particular that on glucose metabolism
and on weight gain, scientific studies report an
improvement of these parameters in women with
a metabolic abnormality, such as women with
PCOS.
The market offers some formulations of
generic pills containing EE and Dienogest. A
“generic” product is a medicinal product, defined
as “essentially similar” to another product whose
patent has expired and whose formulation
is almost the same, while having different
excipients that may affect the absorption of the
active ingredient, side effects, allergic reactions
and intolerances.
As for generic products containing EE and
Dienogest, these are preparations similar to other
V. De Leo.
pills already on the market, in this case OCs sold
abroad and never marketed in Italy. For these
products, the innovative role of Dienogest as a
progestin is emphasized, while the fact that it is
associated with EE and not with natural estrogen
is often minimized. The fact that antiandrogenic
action of EE, exercised through greater liver
stimulation to produce higher levels of SHBG
levels rather than through increased binding
affinity with androgenic steroids, improves
symptoms in women with hyperandrogenism, is
emphasized as well.
As for the control of the menstrual cycle, better
control of uterine bleeding is not guaranteed by
30 mcg of EE, but mainly by the anti-estrogenic
action of Dienogest in the endometrium, that is
similar for both EE oral contraceptives and for
contraceptives containing natural estradiol.
Our clinical experience, paradoxically, has
shown a higher incidence of spotting during the
first two menstrual cycles in women using the
EE/DNG association compared to other pills
containing 30 mcg of EE and different progestins,
just because of this type of mechanism exercised
by Dienogest.
The most important aspect, however, concerns
the different incidence of side effects between
the two types of dienogest-containing OCs.
To understand this difference, it is important
to remember how the two types of estrogen
behave from a pharmacological point of view.
EE is rapidly and completely absorbed following
oral administration. For 30 mcg of EE, the peak
plasma concentration of EE ranges from 90 to 130
pg/ml, 1-2 hours after ingestion. After repeated
administration of EE, there is an increase in blood
levels of EE as early as the 5th day of treatment.
Numerous studies have shown an increase in
plasma levels of EE between 30% and 60% during
a cycle of OCs. Also, EE not binding to SHBG,
is free to circulate in the plasma and binds to
estrogen receptors of the various organs.
E2 is also rapidly and completely absorbed
following oral administration of doses ranging
from 2 to 3 mg. Circulating levels of natural
estrogen are dose dependent. After 2 mg of E2
administered in young women, plasma levels
between 30 and 50 pg/ml are detectable after
8-10 hours, similar to those of an early follicular
phase. Unlike EE, 38% and 60% of the circulating
levels of E2 bind to SHBG and to albumin and,
therefore, only 2% of E2 circulates freely. The
metabolization of E2 is higher in the liver and
in the gastrointestinal tract and about 95% of E2
taken orally is metabolized before entering the
general circulation.
E2 and EE exert their biological effects by
interacting with estrogen receptors (ERα and
ERβ). Based on of this mechanism, it is well
known that the E2 is much less potent than EE
and the difference between these two types of
estrogen is due to this different metabolization.
As for the control of the menstrual cycle,
this problem becomes less important, since
the antiestrogenic action of Dienogest in the
endometrium is very strong, regardless of
circulating estrogen levels. The situation of side
effects for EE/DNG pills and E2/DNG containing
pills, on the other hand, is significantly different.
Based on the foregoing considerations,
comparing the 2 different formulations is a
substantial error. EE/DNG containing pills must
be considered as identical to other pills containing
30 mcg of EE and, therefore, only the E2V/DNG
association is recommended for all women who
had previously discontinued previous the pill
due to its side effects.
A well-established clinical experience in recent
years on the use of this natural pill ensures its
safety and the control of the menstrual cycle and
allowed us to prescribe it to women for whom
EE-containing pills were not recommended and,
in general, to women of any age starting from
adolescence, thanks to its peculiar characteristics.
155
Riassunto delle Caratteristiche del Prodotto
1. DENOMINAZIONE DEL MEDICINALE: MECLON ® “20% + 4% crema vaginale”
MECLON® “200 mg/10 ml + 1 g/130 ml soluzione vaginale”. 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA: Crema vaginale. 100 g contengono: Principi attivi: Metronidazolo 20 g; Clotrimazolo 4 g. Eccipienti: contiene sodio metil p-idrossibenzoato e sodio
propil p-idrossibenzoato. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1.
Soluzione vaginale. Flacone da 10 ml. 10 ml contengono: Principio attivo: Clotrimazolo
200 mg. Flacone da 130 ml. 130 ml contengono: Principio attivo: Metronidazolo 1 g.
Eccipienti: contiene sodio metil p-idrossibenzoato e sodio propil p-idrossibenzoato. Per
l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA:
Crema vaginale. Soluzione vaginale. 4. INFORMAZIONI CLINICHE: 4.1 Indicazioni
terapeutiche: Crema vaginale. Cervico-vaginiti e vulvo-vaginiti causate da Trichomonas
vaginalis anche se associato a Candida albicans, Gardnerella vaginalis ed altra flora
batterica sensibile. MECLON® crema vaginale può essere impiegato anche nel partner
a scopo profilattico. Soluzione vaginale. Coadiuvante nella terapia di cervico-vaginiti,
vulvo-vaginiti causate da Trichomonas vaginalis anche se associato a Candida albicans,
Gardnerella vaginalis ed altra flora batterica sensibile. MECLON® soluzione vaginale può
essere impiegato anche dopo altra terapia topica od orale, allo scopo di ridurre il rischio di
recidive. 4.2 Posologia e modo di somministrazione: Crema vaginale. Somministrare
profondamente in vagina il contenuto di un applicatore una volta al giorno per almeno
sei giorni consecutivi, preferibilmente alla sera prima di coricarsi, oppure secondo prescrizione medica. Nelle trichomoniasi, maggior sicurezza di risultato terapeutico si verifica
con il contemporaneo uso di Metronidazolo per via orale sia nella donna non gestante
che nel partner maschile. Per un’ottimale somministrazione si consiglia una posizione
supina, con le gambe leggermente piegate ad angolo. Per ottenere una migliore sterilizzazione è preferibile spalmare un po’ di MECLON® crema vaginale anche esternamente,
a livello perivulvare e perianale. Se il medico prescrive il trattamento del partner a scopo
profilattico, la crema deve essere applicata sul glande e sul prepuzio per almeno sei
giorni. Istruzioni per l’uso: Dopo aver riempito di crema un applicatore, somministrare la
crema in vagina mediante pressione sul pistone, fino a completo svuotamento. Soluzione
vaginale. Somministrare la soluzione vaginale pronta una volta al giorno, preferibilmente al
mattino, oppure secondo prescrizione medica. Nella fase di attacco l’uso della soluzione
vaginale deve essere associato ad adeguata terapia topica e/o orale. L’irrigazione va
eseguita preferibilmente in posizione supina. Un lento svuotamento del flacone favorirà
una più prolungata permanenza in vagina dei principi attivi e quindi una più efficace
azione antimicrobica e detergente. Istruzioni per l’uso: Dopo aver versato il contenuto
del flaconcino nel flacone, inserire la cannula vaginale sul collo del flacone stesso. Introdurre
la cannula in vagina e somministrare l’intero contenuto. 4.3 Controindicazioni: Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze speciali e
opportune precauzioni d’impiego: Evitare il contatto con gli occhi. Il consigliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni,
effetti collaterali ed avvertenze descritte per il prodotto summenzionato. Evitare il trattamento durante il periodo mestruale. Tenere il medicinale fuori dalla portata e dalla
vista dei bambini. 4.5 Interazioni con altri medicinali e altre forme di interazione:
Nessuna. 4.6 Gravidanza e allattamento: In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico.
4.7 Effetti sulla capacità di guidare veicoli e sull’uso di macchinari: MECLON ®
non altera la capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati:
Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e
Clotrimazolo, le reazioni avverse riscontrate con le formulazioni topiche sono limitate a:
Disturbi del sistema immunitario: Non nota (la frequenza non può essere definita sulla
base dei dati disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto
sottocutaneo: Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito,
dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati
descritti sintomi di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà
farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/
effetti farmacodinamici: Il MECLON ® è una associazione tra Metronidazolo (M) e
Clotrimazolo (C). Il (M) è un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica. Ha effetto trichomonicida diretto ed è attivo su cocchi
Gram-positivi anaerobi, bacilli sporigeni, anaerobi Gram-negativi. Presenta attività spiccata
sulla Gardnerella vaginalis. Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico
con spettro antifungino molto ampio (Candida, etc.). È attivo anche su Trichomonas
vaginalis, cocchi Gram-positivi, Toxoplasmi, etc. È stato documentato che l’associazione
Clotrimazolo-Metronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado
di conseguire tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione
antimicrobica, per sommazione degli effetti dei due principi attivi; 2) Potenziamento
dell’attività antimicotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della
comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che
l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su diversi ceppi di microorganismi è risultata elevata ed è emerso
un potenziamento di essa quando i due principi attivi del MECLON® vengono associati.
5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti
risulta che dopo ripetute applicazioni topiche di MECLON® non si rilevano concentrazioni
apprezzabili di Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella
donna il (M) e il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20%
circa. 5.3 Dati preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel
ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a
dosi molto elevate (600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati).
Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale
(genitale) nel cane e nel coniglio, non ha determinato alcun tipo di lesione nè locale nè
sistemica anche per dosi molte volte superiori a quelle comunemente impiegate in terapia
umana (3-10 Dtd nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per
l’uomo = ca. 3,33 mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato
durante il periodo di gravidanza per via topica vaginale nel coniglio e nel ratto non ha
fatto evidenziare alcun segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi
negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco
degli eccipienti: Crema vaginale. Eccipienti: Stearato di glicole e polietilenglicole; Paraffina liquida; Sodio metile p-idrossibenzoato; Sodio propile p-idrossibenzoato; Acqua
depurata. Soluzione vaginale. Flacone da 10 ml. Eccipienti: Alcool ricinoleilico; Etanolo;
Acqua depurata. Flacone da 130 ml. Eccipienti: Sodio metile p-idrossibenzoato; Sodio
propile p-idrossibenzoato; Acqua depurata. 6.2 Incompatibilità: Non sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: Crema vaginale: 3 anni. Soluzione
vaginale: 3 anni. 6.4 Precauzioni particolari per la conservazione: Questo medicinale
non richiede alcuna particolare condizione per la conservazione. 6.5 Natura e contenuto
del contenitore: MECLON® crema vaginale. Tubo in alluminio verniciato internamente
con resine epossidiche e fenoliche. Gli applicatori monouso sono di polietilene. Tubo da
30 g + 6 applicatori monouso. MECLON® soluzione vaginale. Flaconi di polietilene a
bassa densità; flaconcini di polietilene; cannule vaginali di polietilene. 5 flaconi da 10 ml
+ 5 flaconi da 130 ml + 5 cannule vaginali monouso. 6.6 Precauzioni particolari
per lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERI DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: MECLON® crema vaginale: A.I.C. n. 023703046. MECLON® soluzione
vaginale: A.I.C. n. 023703059. 9. DATA DELLA PRIMA AUTORIZZAZIONE/RINNOVO
DELL’AUTORIZZAZIONE: 11.05.1991 (GU 07.10.1991) / 01.06.2010. 10. DATA DI
REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
20% + 4% crema vaginale, tubo da 30 g + 6 applicatori.
Prezzo: € 12,50.
200 mg/10 ml + 1 g/130 ml soluzione vaginale,
5 flac. 10 ml + 5 flac. 130 ml + 5 cannule. Prezzo: € 13,80.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.
1. DENOMINAZIONE DEL MEDICINALE: MECLON® “100 mg + 500 mg ovuli”. 2.
COMPOSIZIONE QUALITATIVA E QUANTITATIVA: Un ovulo da 2,4 g contiene: Principi
attivi: Metronidazolo 500 mg; Clotrimazolo 100 mg. Per l’elenco completo degli eccipienti, vedere paragrafo 6.1. 3. FORMA FARMACEUTICA: Ovuli. 4. INFORMAZIONI
CLINICHE: 4.1 Indicazioni terapeutiche: Cerviciti, cervico-vaginiti, vaginiti e vulvo-vaginiti da Trichomonas vaginalis anche se associato a Candida o con componente batterica. 4.2 Posologia e modo di somministrazione: Lo schema terapeutico ottimale risulta il seguente: 1 ovulo di MECLON® in vagina, 1 volta al dì. 4.3 Controindicazioni:
Ipersensibilità verso i principi attivi od uno qualsiasi degli eccipienti. 4.4 Avvertenze
speciali e opportune precauzioni d’impiego: Evitare il contatto con gli occhi. Il consigliato impiego contemporaneo di Metronidazolo per via orale è soggetto alle controindicazioni, effetti collaterali ed avvertenze descritte per il prodotto summenzionato.
MECLON® ovuli va impiegato nella prima infanzia sotto il diretto controllo del medico e
solo nei casi di effettiva necessità. Tenere il medicinale fuori dalla portata e dalla vista
dei bambini. 4.5 Interazioni con altri medicinali e altre forme di interazione:
Nessuna. 4.6 Gravidanza e allattamento: In gravidanza il prodotto deve essere impiegato solo in caso di effettiva necessità e sotto il diretto controllo del medico. 4.7 Effetti
sulla capacità di guidare veicoli e sull’uso di macchinari: MECLON® non altera la
capacità di guidare veicoli o di usare macchinari. 4.8 Effetti indesiderati: Dato lo scarso assorbimento per applicazione locale dei principi attivi Metronidazolo e Clotrimazolo,
le reazioni avverse riscontrate con le formulazioni topiche sono limitate a: Disturbi del
sistema immunitario: Non nota (la frequenza non può essere definita sulla base dei dati
disponibili): reazioni di ipersensibilità. Patologie della cute e del tessuto sottocutaneo:
Molto rari (frequenza <1/10.000): fenomeni irritativi locali quale prurito, dermatite allergica da contatto, eruzioni cutanee. L’eventuale manifestarsi di effetti indesiderati comporta l’interruzione del trattamento. 4.9 Sovradosaggio: Non sono stati descritti sintomi
di sovradosaggio. 5. PROPRIETÀ FARMACOLOGICHE: 5.1 Proprietà farmacodinamiche: Categoria farmacoterapeutica: Antinfettivi ed antisettici ginecologici/Associazioni
di derivati imidazolici - Codice ATC: G01AF20. Meccanismo d’azione/effetti farmacodinamici: Il MECLON® è una associazione tra metronidazolo (M) e clotrimazolo (C). Il (M) è
un derivato nitroimidazolico ad ampio spettro di azione antiprotozoaria e antimicrobica.
Ha effetto trichomonicida diretto ed è attivo su cocchi Gram-positivi anaerobi, bacilli
sporigeni, anaerobi Gram-negativi. Presenta attività spiccata sulla Gardnerella vaginalis.
Non è attivo sulla flora acidofila vaginale. Il (C) è un imidazolico con spettro antifungino
molto ampio (Candida, etc.). È attivo anche su Trichomonas vaginalis, cocchi Grampositivi, Toxoplasmi, etc. È stato documentato che l’associazione ClotrimazoloMetronidazolo dà luogo ad effetti di tipo additivo, pertanto essa è in grado di conseguire
tre vantaggi terapeutici principali: 1) Ampliamento dello spettro d’azione antimicrobica,
per sommazione degli effetti dei due principi attivi; 2) Potenziamento dell’attività antimi-
cotica, antiprotozoaria ed antibatterica; 3) Abolizione o ritardo della comparsa dei fenomeni di resistenza. Studi microbiologici in vitro hanno dimostrato che l’attività trichomonicida e antimicotica risulta potenziata quando il (M) e il (C) sono associati nelle stesse
proporzioni che sono presenti nel MECLON®. Anche l’attività antibatterica esaminata su
diversi ceppi di microorganismi è risultata elevata ed è emerso un potenziamento di essa
quando i due principi attivi del MECLON® vengono associati. 5.2 Proprietà farmacocinetiche: Dalle indagini farmacocinetiche sui conigli, cani e ratti risulta che dopo ripetute
applicazioni topiche di MECLON® non si rilevano concentrazioni apprezzabili di
Clotrimazolo e Metronidazolo nel sangue. Per applicazione vaginale nella donna il (M) e
il (C) vengono assorbiti in una percentuale che varia tra il 10% e il 20% circa. 5.3 Dati
preclinici di sicurezza: La tossicità acuta del MECLON® nel topo e nel ratto (os) è risultata molto bassa, con una mortalità di appena il 20% dopo 7 giorni, a dosi molto elevate
(600 mg/Kg di (C) e 3000 mg/Kg di (M), sia da soli che associati). Nelle prove di tossicità subacuta (30 giorni) il MECLON®, somministrato per via locale (genitale) nel cane e
nel coniglio, non ha determinato alcun tipo di lesione nè locale nè sistemica anche per
dosi molte volte superiori a quelle comunemente impiegate in terapia umana (3-10 Dtd
nel cane e 100-200 Dtd nel coniglio; 1 Dtd = dose terapeutica/die per l’uomo = ca. 3,33
mg/Kg di (C) e ca. 16,66 mg/Kg di (M)). Il MECLON® somministrato durante il periodo di
gravidanza per via topica vaginale nel coniglio e nel ratto non ha fatto evidenziare alcun
segno di sofferenza fetale per dosi die di 100 Dtd, nè influssi negativi sullo stato gestazionale. 6. INFORMAZIONI FARMACEUTICHE: 6.1 Elenco degli eccipienti: Eccipienti:
Miscela idrofila di mono, di, tri-gliceridi di acidi grassi saturi. 6.2 Incompatibilità: Non
sono note incompatibilità con altri farmaci. 6.3 Periodo di validità: 3 anni. 6.4
Precauzioni particolari per la conservazione: Questo medicinale non richiede alcuna
particolare condizione per la conservazione. 6.5 Natura e contenuto del contenitore:
10 ovuli in valve in PVC, racchiusi in scatola di cartone. 6.6 Precauzioni particolari per
lo smaltimento e la manipolazione: Nessuna istruzione particolare. 7. TITOLARE
DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN COMMERCIO: ALFA WASSERMANN
S.p.A. - Sede legale: Via E. Fermi, n. 1 - Alanno (PE). Sede amministrativa: Via Ragazzi
del ‘99, n. 5 - Bologna. 8. NUMERO DELL’AUTORIZZAZIONE ALL’IMMISSIONE IN
COMMERCIO: A.I.C. n. 023703010. 9. DATA DELLA PRIMA AUTORIZZAZIONE/
RINNOVO DELL’AUTORIZZAZIONE: 27.11.1978 (GU 16.01.1979) / 01.06.2010.
10. DATA DI REVISIONE DEL TESTO: Determinazione AIFA del 27 Ottobre 2010.
100 mg + 500 mg ovuli, 10 ovuli. Prezzo: € 12,50.
Medicinale non soggetto a prescrizione medica (SOP). CLASSE C.