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Italian Journal
of
Gynaecology
& Obstetrics
March 2017 - Vol. 29 - N. 1 - Supplement - ISSN 2385 - 0868
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Supplement
Idipharma Award
“Four best original works relating to
the development of knowledges on the
reepithelization action of TIAGIN®”
Partner-Graf
1
Italian Journal
of
Gynaecology
& Obstetrics
The Official Journal of the
Società Italiana di Ginecologia e Ostetricia
(SIGO)
Supplement
Idipharma Award
“Four best original works relating to
the development of knowledges on the
reepithelization action of TIAGIN®”
Partner-Graf
Editor in Chief
Scollo Paolo, Catania
Editors
Valensise Herbert, Roma
Vizza Enrico, Roma
Editorial Board
Cervigni Mauro, Roma
Chiantera Vito, Palermo
Costa Mauro, Genova
De Stefano Cristofaro, Avellino
De Vita Davide, Salerno
Ercoli Alfredo, Novara
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
Zerbinati Roberto
Zerbinati Serena
Management, Administrative office
Partner-Graf Srl - Via F. Ferrucci, 73 - 59100 Prato
Tel 0574 527949 - Fax 0574 636250
E-mail: [email protected]
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It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
Table of contents
5
Effects of micro-crystals of titanium dioxide with covalently bound silver ions
and extracts of Aloe Barbadensis (TIAGIN®) on Vaginal Health Index Score
(VHIS) and Female Sexual Function Index (FSFI) in patients affected by vaginal
disepithelization: a prospective, single-center cohort analysis
7
Role of vaginal TIAGIN® in cervical reepithelialization and high-risk HPV
clearance in patients with low-grade cervical lesions
13
Efficacy of TIAGIN® on post-operative reepithelialization in women subjected
to cervical surgery (LEEP or laser cone biopsies): case-control study
17
Colposcopy and cytology after treatment with TIAB® system and hyaluronic
acid-based vaginal capsules in patients who have undergone cervical surgery
due to an HPV-related disease
25
Antonio Simone Laganà, Benito Chiofalo, Roberta Granese, Vittorio Palmara, Onofrio Triolo
Caterina Ricci
Anna Daniela Iacobone, Eleonora Petra Preti, Ailyn Mariela Vidal Urbinati, Eugenia Tomás Roldán
Giada Lavitola, Nicoletta De Rosa, Ilaria Morra, Carmine Nappi, Giuseppe Bifulco
5
Italian Journal of
Gynaecology & Obstetrics
March 2017 - Vol. 29 - N. 1 - Quarterly - ISSN 2385 - 0868
Effects of titanium dioxide microcrystals with covalently bonded silver
ions and Aloe Vera extract (TIAGIN®) on the Vaginal Health Index
Score (VHIS) and Female Sexual Function Index (FSFI) in patients with
vaginal de-epithelialization: a prospective, single-center cohort analysis
Antonio Simone Laganà1, Benito Chiofalo1, Roberta Granese1, Vittorio Palmara1, Onofrio
Triolo1
Gynecology and Obstetrics Unit, Department of Human Pathology in Adulthood and Childhood
“G. Barresi”, University of Messina, Messina, Italy
1
ABSTRACT
Objective: to evaluate the effects of titanium dioxide
microcrystals with covalently bonded silver ions and
Aloe Vera extract (TIAGIN®) on the Vaginal Health
Index Score (VHIS) and Female Sexual Function Index
(FSFI) in patients with vaginal de-epithelialization.
Materials and methods: we enrolled 45 postmenopausal women with vaginal de-epithelialization,
who underwent VHIS evaluation and completed
an FSFI test. We recorded their age, age at onset of
menopause, parity and Body Mass Index. After this
baseline evaluation, patients underwent 30 days of
vaginal treatment with one capsule per day of TIAGIN®.
After treatment, all patients were evaluated again using
the same methods as the pre-treatment phase.
Results: after treatment there was significant
improvement in all VHIS parameters (elasticity, fluid
secretion type and consistency, pH, epithelialization
of vaginal mucosa, and moisture) and in the total score
(p=0.006). Similarly, after treatment there was also a
significant improvement in 4 FSFI areas (lubrication,
orgasm, satisfaction, and pain) and in the total score
(p=0.005). None of the patients reported any local or
systemic side effects during treatment.
Conclusions: we observed a significant improvement in
both the VHIS and FSFI, which can be considered direct
and indirect signs of increased vaginal epithelialization
following vaginal treatment with TIAGIN®.
SOMMARIO
Obiettivo: valutare gli effetti di microcristalli di biossido
di titanio con ioni d’argento covalentemente legati ed
estratti di Aloe Barbadensis (TIAGIN®) sul Vaginal
Health Index Score (VHIS) e Female Sexual Function
Index (FSFI) in pazienti affette da disepitelizzazione
vaginale.
Materiali e metodi: abbiamo arruolato 45 donne in
post-menopausa affette da disepitelizzazione vaginale,
valutate mediante VHIS e FSFI. Abbiamo registrato età,
età di insorgenza della menopausa, parità e Body Mass
Index. Dopo la valutazione iniziale, le pazienti sono state
trattate con una capsula vaginale al giorno di TIAGIN®,
per 30 giorni. Dopo il trattamento, tutte le pazienti sono
state rivalutate usando la stessa metodologia applicata
durante la valutazione iniziale pre-trattamento.
Risultati: dopo il trattamento abbiamo osservato un
miglioramento significativo di tutti i parametri del
VHIS (elasticità, tipo e consistenza della secrezione, pH,
epitelizzazione e umidificazione della mucosa vaginale)
e dello score totale (p=0.006). Parallelamente, abbiamo
osservato anche un miglioramento di 4 domini del
FSFI (lubrificazione, orgasmo, soddisfazione, dolore) e
dello score totale (p=0.005). Nessuna delle pazienti ha
riportato effetti indesiderati locali o sistemici durante il
trattamento.
Conclusioni: i nostri dati dimostrano significativi
miglioramenti sia del VHIS che del FSFI, che possono
essere considerati segni indiretti dell’aumentata
epitelizzazione vaginale dopo trattamento con TIAGIN®.
Keywords: Aloe Vera, silver ions, Vaginal Health Index
Score, Female Sexual Function Index (FSFI), vaginal
de-epithelialization.
Corresponding to: [email protected]
Copyright 2017, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-61
7
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
INTRODUCTION
8
There is mounting evidence to suggest that
sexual health plays a pivotal role throughout
women’s lives, from puberty to the postmenopausal period(1,2). According to the World
Health Organization, sexual health requires a
positive approach to human sexuality and an
understanding of the complex factors that shape
human sexual behavior(3). Despite the need for
more epidemiological research into female sexual
dysfunction (FSD), it is widely acknowledged
that it increases as women age and affects
about 40-45% of adult women(4). To this regard,
common risk factor categories associated with
FSD include individual general state of health,
diabetes mellitus, cardiovascular disease, other
genitourinary diseases, psychiatric/psychological
disorders, other chronic diseases, and sociodemographic conditions (5-8). Nevertheless, the
multidimensional nature of human sexuality may
also play a detrimental part in objectifying the real
contributing factors to possible dysfunctions(9,10).
On the basis of these elements, several
approaches and methods have already been
proposed in order to recognize and measure sexual
health, FSD rate, and severity. As has been widely
reviewed by Rosen(11), on one hand objective
measures, such as vaginal photoplethysmography
or Duplex ultrasound, have been used in
some studies but lack standardization and are
unsuitable for use in large-scale clinical trials,
while on the other hand, self-reported event logs
or questionnaires are best suited for research or
clinical assessment of female sexual function.
Among these questionnaires, one of most used
and validated is the Female Sexual Function Index
(FSFI)(12), which consists of 19 items designed to
asses 6 important areas of female sexuality: desire,
arousal, lubrication, orgasm, satisfaction, and
pain. In addition to these important determining
factors, numerous studies have reported that
adequate vaginal epithelialization is strictly
related to satisfactory quantity and quality
of sexual activity(13), even after autologous in
vitro cultured vaginal tissue transplantation in
patients with Meyer-von-Rokitansky-KüsterHauser syndrome(14,15). Like the FSFI, the need
for an objective and measurable evaluation of
vaginal mucosa led to the development of the
Vaginal Health Index Score (VHIS)(16), which
analyzes overall elasticity, fluid secretion type
and consistency, pH, epithelialization of vaginal
mucosa, and moisture.
Several pharmacological treatments have
already been developed to improve vaginal
TIAGIN®’s effect on vaginal de-epithelialization
epithelialization and, consequently, sexual health
in the female population (17,18). Nevertheless,
current data is still not sufficient to draw any
firm conclusions regarding the gold standard
treatment. Recent evidence reported that Aloe
Vera extracts have significant antioxidant (19),
antibacterial(20), anti-inflammatory, and woundhealing properties (21). Furthermore, similar
beneficial properties were reported for silver
ions(22-24).
Considering these elements and the lack of
robust available data in literature, the aim of the
current study is to evaluate the effects of titanium
dioxide microcrystals with covalently bonded
silver ions and Aloe Vera extract (TIAGIN ®)
on the VHIS and FSFI in patients with vaginal
de-epithelialization.
MATERIALS AND METHODS
We performed a prospective, single-center
cohort analysis between March and May 2016 at
the Gynecology and Obstetrics Unit, Department
of Human Pathology in Adulthood and Childhood
“G. Barresi”, University of Messina (Messina,
Italy). We enrolled post-menopausal women
with vaginal de-epithelialization, excluding
patients with significant comorbidities (chronic
cardiovascular, immune, endocrine, and metabolic
disorders, and cancers) and patients who had
used any other kind of pharmacological treatment
(including the substances tested in this study)
during the previous 3 months.
The study design complies with the Declaration
of Helsinki, conforms to the Committee
on Publication Ethics (COPE) guidelines
(http://publicationethics.org), and was approved
by the Institutional Review Board (IRB) of the
hospital where it was performed. Each patient
who participated in this study was fully informed
of the procedures involved and signed a consent
form for data collection for research purposes.
All the design, analysis, data interpretation,
drafting, and revision processes complied with
the Strengthening the Reporting of Observational
Studies in Epidemiology (STROBE) Statement:
guidelines for reporting observational studies(25),
available through the EQUATOR (Enhancing the
QUAlity and Transparency Of health Research)
network (http://www.equator-network.org).
For all the enrolled patients, we recorded age,
age at onset of menopause, parity, and Body Mass
Index (BMI). All the patients underwent VHIS
Antonio Simone Laganà et al..
TIAGIN®’s effect on vaginal de-epithelialization
evaluation (as described by Bachmann et al.)
(16)
, always performed by the same gynecologist
in order to avoid inter-observer variability, and
completed the FSFI test.
After this baseline evaluation, all the enrolled
patients underwent 30 days of vaginal treatment
with one capsule per day of titanium dioxide
microcrystals with covalently bonded silver ions
and Aloe Vera extract (TIAGIN®). Any patient
taking less than 80% of the allocated dose of study
drug was regarded as noncompliant and excluded
from the study. The study drug was supplied free
of charge and none of the enrolled patients were
paid to join or continue the study.
After treatment, all the patients were evaluated
again using the same methods as the pre-treatment
phase (VHIS evaluation by the same gynecologist
who performed it during the pre-treatment phase
and self-reported FSFI). All the side effects were
recorded and an independent data safety and
monitoring committee evaluated the study results.
Statistical analyses were performed by using
the SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA)
software package. The assumption of normal
distribution for continuous variables was tested
with the Kolmogorov–Smirnov test for goodness
of fit. Continuous variables were compared
between pre- and post-treatment phases using the
Student t-test. A p-value of <0.05 was considered
statistically significant.
RESULTS
We enrolled 45 patients who met the inclusion/
exclusion criteria and signed an informed consent
form. Age, age at onset of menopause, parity,
and BMI are reported in Table 1. All the patients
declared that they took at least 90% of the allocated
dose of study drug (good compliance).
Table 1.
Characteristics of enrolled patients
Mean ± Standard
Deviation
Age
Age of menopause onset
Parity
Body Mass Index
56.9 ± 10.0
48.8 ± 2.9
2.3 ± 0.8
23.8 ± 3.2
Pre- and post-treatment VHIS results are
reported in Table 2, whereas results for FSFI are
reported in Table 3. In particular, after treatment
there was a significant improvement in all VHIS
parameters (elasticity, fluid secretion type and
consistency, pH, epithelialization of vaginal
mucosa, and moisture) and in the total score
(p=0.006). Similarly, after the treatment there was
also a significant improvement in 4 FSFI areas
(lubrication, orgasm, satisfaction, and pain) and in
the total score (p=0.005), whereas the improvement
for the remaining 2 areas (desire, arousal) was not
significant (p=0.126 and p=0.082, respectively).
None of the patients reported any local or systemic
side effects during treatment.
Table 2.
Comparison of Vaginal Health Index Score between pre-treatment and post-treatment phases.
Vaginal Health
Index parameters
Pre-treatment
(Mean ± Standard Deviation)
Post-treatment
(Mean ± Standard Deviation)
p
Elasticity
2.4 ± 0.8
2.7 ± 0.5
0.036
Fluid Secretion type and consistency
2.0 ± 0.8
2.3 ± 0.5
0.036
pH
2.3 ± 0.8
2.6 ± 0.6
0.047
Epithelial mucosa
2.3 ± 0.8
2.6 ± 0.5
0.036
Moisture
2.6 ± 0.7
2.9 ± 0.7
0.045
Vaginal Health Index Score
11.6 ± 3.0
13.1 ± 1.9
0.006
Pre-treatment
(Mean ± Standard Deviation)
Post-treatment
(Mean ± Standard Deviation)
p
Desire
3.7 ± 1.1
4.0 ± 0.7
0.126
Arousal
3.2 ± 0.7
3.4 ± 0.3
0.082
Lubrication
2.8 ± 0.7
3.1 ± 0.4
0.014
Orgasm
3.3 ± 1.0
3.7 ± 0.7
0.031
Satisfaction
3.8 ± 0.8
4.1 ± 0.4
0.027
Pain
2.8 ± 1.3
3.3 ± 0.7
0.024
Female Sexual Function
Index score
19.5 ± 3.9
21.4 ± 2.0
0.005
Table 3.
Comparison of Female Sexual Function Index between pre-treatment and post-treatment phases.
Female Sexual Function
Index parameters
9
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
DISCUSSION
10
TIAGIN®’s effect on vaginal de-epithelialization
Sexual wellbeing has attracted growing
attention and increased in importance over recent
decades, both for men and women. Since the
first pioneering studies in 1960, researchers have
taken many steps forward in understanding the
complex mechanisms behind female sexuality(26,27).
In addition to the important psychological aspects
that may affect it(28), there is mounting evidence
to suggest that the vaginal microenvironment
plays a pivotal role in modulating moisture
and pain perception during intercourse (29-31).
Although vaginal cytokine levels are not linked to
postmenopausal vulvovaginal symptoms(32), it is
possible that hormonal modifications (especially
in post-menopause) may alter the vaginal
microbiome and leukocyte polarization(33,34), two
key elements responsible for pain modulation(35).
Several treatments have already been
developed to improve vaginal epithelialization
and ameliorate related symptoms and signs(36-38),
although the available studies differ significantly
in terms of the methods used and thus in the
results obtained, making it difficult to identify the
best approach. Very few studies have investigated
the effects of Aloe and silver ions on the vaginal
microenvironment, although this data could
be misinterpreted since in most studies the
researchers mixed these two compounds with
others(39), or data analysis was based on animal
models(40). To the best of our knowledge, this is
the first report on the effects of silver ions and
extracts of Aloe Vera in patients with vaginal
de-epithelialization.
Our analysis demonstrated a significant
improvement in both the VHIS (p=0.006) and FSFI
(p=0.005), which can be considered direct (VHIS)
and indirect (FSFI) signs of increased vaginal
epithelialization. On the one hand, all the most
important vaginal health parameters increased,
whereas on the other hand the latter indirectly
ameliorated female sexual functions. Indeed, all
the FSFI parameters increased significantly, with
the exception of desire and arousal, which may
be more dependent on the patient’s psychological
state(41).
Despite our significant results, the study was
affected by several limitations. Firstly, we did not
use a control group, although we opted for this
study design since it would have been unethical
not to provide any therapy to patients with
vaginal de-epithelialization or to administer them
a placebo. Moreover, our study was not blind,
so patients and researchers were all aware of the
purpose of the investigation and the drugs being
used. What is more, our analysis was limited to the
post-menopausal period and the study population
was quite small.
Considering these latter elements, we would
like to take this opportunity to encourage future
studies with greater statistical power, which
may confirm our results within larger cohorts.
Furthermore, future research should explore
whether treatment with silver ions and Aloe
Vera extract could increase vaginal fluid levels of
platelet-derived growth factor (PDGF), vascular
endothelial growth factor (VEGF) and fibroblast
growth factor (FGF), which are the most important
mediators responsible for re-epithelialization.
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DECLARATION OF INTEREST
This study did not receive any grants or
funding. The authors have no proprietary,
financial, professional, or other personal interest
of any nature in any product, service, or company.
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11
Italian Journal of
Gynaecology & Obstetrics
March 2017 - Vol. 29 - N. 1 - Quarterly - ISSN 2385 - 0868
Role of TIAGIN® vaginal formulation in cervical reepithelialization and
high-risk HPV clearance in patients with low-grade cervical lesions
Caterina Ricci1
1
Polo Salute della Donna e del Bambino, Fondazione Policlinico Universitario A. Gemelli - U.C.S.C.- Rome Director: Prof. Giovanni Scambia
ABSTRACT
Background: high-risk HPV infection, particularly when
associated with a low-grade cervical lesion, is a very
common problem, especially in young women. It is
often associated with the presence of cervical ectropion/
ectopy, which causes bleeding and consequent anxiety
and discomfort for the patient. The use of a molecule
able to trigger the reparatory processes of the cervical
epithelium, while also providing antibacterial action and
boosting the local physiological immune response, could
be a valid aid for the clinical management of such cases.
Objective: to evaluate the reepithelialising action and
efficacy of TIAGIN® vaginal formulation in a group of
patients with low-grade cervical lesions (ASC-US /L-SIL)
positive for high-risk HPV with cervical ectropion/
ectopy, treated with TIAGIN® vaginal formulation,
by analysing the cytological clearance percentage, the
HPV clearance percentage, any regression of the lesions
visible during colposcopy and the degree of ectropion/
ectopy reepithelialisation at 6 months.
Results: data was collected from 19 patients, with a
mean age of 31. Almost all the patients managed to
complete the prescribed treatment. Only 1 of the 19
patients stopped treatment after the first cycle due to
intolerance to the product and was therefore excluded
from the analysis, conducted on 18 patients. The
cytology check-up at 6 months after treatment with
TIAGIN® vaginal formulation was negative in 12 out of
18 patients (66.7%), while the microbiological clearance
rate at 6 months after treatment was 50% with 9 negative
HPV tests out of 18. At 6 months, 9 out of 18 patients
(50%) had negative colposcopy results following
complete regression of the AT1. In the remaining 50%,
the colposcopy results were unchanged or improved,
without any progression or the need for a biopsy.
Bleeding had stopped in all patients at the 6-month
check-up. In 5 patients (27.8%), the ectropion/ectopy
was unchanged compared to T0. In 3 patients (16.6%),
it was at least 25% smaller. In 10 patients (55.6%) it was
resolved and completely reepithelialised.
Corresponding to: [email protected]
Copyright 2017, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-62
Conclusions: in clinical practice, vaginal TIAGIN®
vaginal formulation has shown itself to be a promising
therapeutic aid in the management of low-grade
cervical lesions caused by high-risk HPV, and is a valid
option for the conservative management of bleeding
ectropion/ectopy. Although this data is very interesting
and promising, further evaluation and validation is
required from prospective studies involving a larger
number of subjects.
Keywords: Aloe Barbadensis, silver ions, Vaginal Health
Index Score, Female Sexual Function Index (FSFI), vaginal
disepithelization.hormone.
SOMMARIO
Introduzione: l’infezione da HPV ad alto rischio,
in particolare associata a una lesione cervicale di
basso grado è una problematica attualmente molto
diffusa, specie nelle giovani donne. Ad essa spesso si
associa la presenza di un ectropion/ectopia, causa di
sanguinamento e conseguente ansia e sconforto per
la paziente. L’utilizzo di una molecola che riesca ad
innescare i processi riparativi dell’epitelio cervicale,
svolgendo anche un’azione antibatterica, e a coadiuvare
la risposta immunitaria fisiologica locale, potrebbe
rappresentare un valido aiuto nella gestione clinica.
Obiettivi: valutare l’azione riepitelizzante e l’efficacia
di TIAGIN® formulazione vaginale in un gruppo di
pazienti con lesioni di basso grado della cervice uterina
(ASC-US /L-SIL) positive ad HPV ad alto rischio con
ectropion/ectopia cervicale, trattate con TIAGIN® per
applicazione vaginale, analizzando la percentuale
di negativizzazione della citologia, la percentuale di
negativizzazione dell’HPV test, l’eventuale regressione
delle lesioni colposcopicamente visibili e il grado di
riepitelizzazione dell’ectropion/ectopia a 6 mesi,
Risultati: sono stati raccolti i dati relativi a 19 pazienti
con età media di 31 anni. La quasi totalità delle pazienti
è riuscita a portare a termine la terapia prescritta;
solo 1 paziente su 19 ha sospeso il trattamento dal
primo ciclo per intolleranza al prodotto ed è stata
quindi esclusa dall’analisi, condotta su 18 pazienti.
La citologia di controllo a 6 mesi dopo terapia con
13
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
Role of TIAGIN® in the management of patients affected by low-grade lesions of the uterine cervix
TIAGIN® formulazione vaginale è risultata negativa in
12 pazienti su 18 (66,7%). Il tasso di negativizzazione
microbiologica a 6 mesi dopo terapia è risultato del
50% con 9 negativizzazioni dell’HPV test su 18. Al
tempo 6 mesi 9 pazienti su 18 (50%) mostravano una
negativizzazione del quadro colposcopico in termini
di regressione completa della TA1. Nel restante 50% il
quadro colposcopico è risultato invariato o ridotto in
estensione, senza alcuna progressione o necessità insorta
di prelievo bioptico. Tutte le pazienti hanno mostrato al
controllo a 6 mesi una risoluzione del sanguinamento.
In 5 pazienti (27,8%) l’ectropion/ectopia risultava
invariato rispetto al T0. In 3 pazienti (16,6%) risultava
ridotto in dimensioni di almeno il 25%. In 10 pazienti
(55,6%) risultava risolto e completamente riepitelizzato.
Conclusioni: TIAGIN® formulazione vaginale si è
mostrato nella pratica clinica un promettente supporto
terapeutico nella gestione delle lesioni di basso grado
della cervice uterina causate da HPV ad alto rischio,
e una valida opzione nella gestione conservativa
dell’ectropion/ectopia sanguinante. Tali dati, seppur
interessanti e promettenti, necessitano di valutazioni e
ulteriori validazioni in studi prospettici su più ampio
campione.
Parole chiave:
Ectropion, HPV
Riepitelizzazione,
ASC-US/L-SIL,
BACKGROUND
14
High-risk HPV infection, particularly when
associated with a low-grade cervical lesion, is
a very common problem, especially in young
women. These lesions are known to present a
significant possibility of spontaneous regression,
meaning that conservative and observational
management is often an option.(1) The presence
of cervical ectropion/ectopy, which causes
bleeding and consequent anxiety and discomfort
for the patient, is also very widespread and often
occurs alongside the lesions. Gynaecologists and
colposcopists are routinely required to manage
these problems on an outpatient basis.
The role played by the local vaginal
immune system in determining the regression/
progression of HPV-related lesions having been
amply demonstrated in literature(2-3), the use of a
molecule able to trigger the reparatory processes
of the cervical epithelium while also providing
antibacterial action and boosting the local
physiological immune response, could be a valid
aid for the clinical management of such cases.
The TIAB® complex (titanium dioxide with
covalently linked monovalent silver ions) is a
nanotechnology product contained in TIAGIN®
for vaginal application and foam for vulvar
application. It kills the microorganisms in question,
particularly fungi, bacteria and viruses, through a
twofold mechanism: by blocking the enzymatic
respiratory system through interaction with the
ribosome; by damaging the cell wall and making it
permeable. This complex has been shown to act on
650 microorganisms in the vagina and possesses
considerable reepithelialising potential(4-5).
In vitro studies have particularly highlighted
the antiviral potential of silver nanoparticles
thanks to their interaction with membrane viral
glycoproteins. In fact, by bonding to them and
changing their three-dimensional structure by
altering the S-S bonds, they reduce the opportunity
for the virus to enter the host cell(6). In greater
detail, a study conducted in 2011 demonstrated
the antiviral activity of silver nanoparticles on
a cervical cell culture model with regard to the
HIV-1 virus by means of various mechanisms:
TNF-alpha reduction, stimulation of lymphocyte
production and immune cell activation(7).
However, there are no studies in literature
designed to establish the possible efficacy of this
complex on cervical lesions caused by high-risk
HPV.
OBJECTIVE
The study objective was to evaluate the
reepithelialising action and efficacy of TIAGIN®
vaginal formulation as an adjuvant in the
resolution of HPV-related low-grade cervical
lesions in a group of patients with low-grade
cervical lesions (ASC-US /L-SIL) positive for
high-risk HPV with cervical ectropion/ectopy.
We particularly analysed the cytological clearance
percentage, the HPV clearance percentage, the
regression of lesions visible during colposcopy and
the degree of reepithelialisation of the ectropion/
ectopy at 6 months.
SETTING
Colposcopy Clinic, University Hospital.
Role of TIAGIN® in the management of patients affected by low-grade lesions of the uterine cervix
MATHERIALS AND METHODS
Data was gathered on 19 patients with a
mean age of 31 (20-62 years old), who attended
the Colposcopy Clinic between December 2015
and August 2016, all of whom were suffering
from low-grade cervical lesions (ASC-US
/L-SIL) positive for high-risk HPV with cervical
ectropion/ectopy, treated with TIAGIN® vaginal
formulation. The patients, assessed during an
initial visit (Time 0), all met the following criteria:
Pap test indicative of low-grade lesions (ASC-US
/L-SIL), colposcopy with evidence of bleeding
ectropion/ectopy, HPV test positive for high-risk
genotypes. The exclusion criteria were: pregnancy,
use of other immune system adjuvant therapies,
previous cervical treatments. The patients
underwent a colposcopy at T0 and T6 months,
performed by the same SICPCV-accredited
colposcopists. At T0, all 18 patients showed an
AT1 (abnormal transformation zone suggestive of
a low-grade lesion in accordance with the SICPCV
classification)(8) on the type 1 transformation
zone (fully visible ectocervical squamocolumnar
junction as per the IFCPC 2011 classification)(9)
associated with bleeding ectropion/ectopy. The
patients were treated on the basis of the following
dosage regimen: TIAGIN® vaginal formulation
1/day for 10 days a month for 4 months. They
were then reassessed after 6 months (Time 6m),
when the Pap test, colposcopy and HPV test were
repeated. Traditional cytology and Multiplex HPV
PCR tests were used in the study, in keeping with
routine clinical practice at the facility. The patients
were permitted to replace TIAGIN® capsules
with TIAGIN® vaginal softgel capsules when the
product was launched on the market and replaced.
Caterina Ricci
due to intolerance to the product in the form of
localised itching and was therefore excluded
from the analysis, conducted on 18 patients. All
the patients demonstrated a preference for the
TIAGIN® softgel formulation and found it easier
to use than the TIAGIN® capsules used during the
first treatment cycles.
At T0 the cytology results showed 13 patients
with L-SIL and 5 patients with ASC-US. The
follow-up cytology assessment at 6 months after
treatment with TIAGIN® vaginal formulation
was negative in 12 out of 18 patients (66.7%), with
all the ASC-US cytology tests and 7 of the L-SIL
cytology tests coming back negative. All the study
patients had an HPV test at T0 that was positive
for high-risk genotypes (the 18 patients were
found to have 9 different genotypes, with 2 cases
of multiple infection).
The microbiological clearance rate at 6 months
after treatment was 50%, with 9 cases of clearance
out of 18. The colposcopy examinations found
all 18 patients to have an AT1 associated with
bleeding ectropion/ectopy at T0. At 6 months, 9
of the 18 patients (50%) were found to be negative
during the colposcopy due to complete regression
of the AT1. In the remaining 50%, the colposcopy
results were unchanged or improved, without any
progression or the need for a biopsy.
Bleeding had stopped in all patients at the
6-month check-up. In 5 patients (27.8%), the
ectropion/ectopy was unchanged compared to T0.
In 3 patients (16.6%), it was at least 25% smaller. In
10 patients (55.6%) it was resolved and completely
reepithelialised.
These results are summed up in Table 1 and Fig. 1.
Table 1.
Cytological, colposcopic and microbiological response in 18 patients
OUTCOMES
The outcomes we evaluated were the
cytological clearance percentage, the HPV
clearance percentage, any regression of lesions
visible during colposcopy and the degree of
reepithelialisation of the ectropion/ectopy at 6
months. This outcome was evaluated as: complete
resolution, partial regression or unchanged
appearance compared to T0.
RESULTS
Almost all the patients managed to complete
the prescribed treatment. Only 1 of the 19
patients stopped treatment after the first cycle
Figure 1
Degree of ectropion/ectopy reepithelialization
15
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
Role of TIAGIN® in the management of patients affected by low-grade lesions of the uterine cervix
DISCUSSION
The findings in our study seem promising
given the high rate of cytological, microbiological
and also colposcopic regression of the HPV-related
low-grade cervical lesions in the group analysed
after treatment with TIAGIN® vaginal formulation.
These results are more or less comparable with the
spontaneous regression data present in literature
and superior as regards the rate of spontaneous
cytological and microbiological regression(10-12).
The findings regarding the rate of ectropion/
ectopy reepithelialisation are also significant for
clinical management purposes, with bleeding
being resolved in all cases and complete
reepithelialisation of the ectropion/ectopy being
achieved in 55.6%.
These results also appear promising in
consideration of the lack of studies reported in
literature regarding a conservative, therapeutic
approach to the medical management of
ectropion/ectopy. This study is certainly limited
by its small population and relatively short time
scale, considering the natural history of HPV
16
REFERENCES
1) Natural history and epidemiology of HPV infection
and cervical cancer. Castellsaguè X. Gynecol Oncol
2008; 110(3 Suppl 2):S4-7.
2) Role of Innate Immunity against Human
Papillomavirus (HPV) Infections and Effect of
Adjuvants in Promoting Specific Immune Response.
Alfredo Amador-Molina, et al. Viruses. 2013 Nov; 5(11):
2624-2642.
3) Immune responses to human papilloma viruses.
Stanley MA. Indian J Med Res 2009;130:266-76.
4) Evaluation of the efficacy of titanium dioxide with
monovalent silver ions covalently linked (TIAB®)
as an adjunct to scaling and root planning in the
management of chronic periodontitis using pcr
analysis: a microbiological study. Lauritano D, et al.
J boil regul homeost agents. 2015 jul-sep;29(3 suppl 1):
127-30.
5) TIAGIN® Capsule vaginali foglietto illustrativo
6) Silver nanoparticles as Potential Antiviral Agents.
Galdiero S. et al. Molecules 2011, 16 8894-8918.
infection that underlies low-grade cervical lesions.
On the other hand, it offers an interesting starting
point for studies involving a larger population and
tangible support for the clinical use of TIAGIN® in
the analysed setting.
CONCLUSIONS
In its vaginal formulations TIAGIN® has
shown itself to be a promising therapeutic aid in
the clinical management of low-grade cervical
lesions caused by high-risk HPV, thanks also to its
good tolerability and ease of use, especially in the
softgel formulation.
It has also been shown to be a valid option
for the conservative management of bleeding
ectropion/ectopy. Although this data is very
interesting and promising, further evaluation and
validation is required from prospective studies
involving a larger number of subjects.
7) Silver nanoparticles are broad-spectrum bactericidal
and virucidal compounds. Lara HH et al. Journal of
Nanobiotechnology 2011, 9:30.
8) SICPCV: gestione della paziente con pap-test
anormale. Linee Guida Edizione 2006. Anno XXI; N. 1
Dicembre 2006.
9) 2011 colposcopic terminology of the International
Federation for cervical Pathology and Colposcopy.
Bornstein J et al. Obstet Gynecol. 2012 Jul; 120(1):166-72.
10) Human Papillomavirus Infection and Time to
Progression and Regression of Cervical Intraepithelial
Neoplasia. Nicolas F. Schlecht, et al. Jnl of Natl Cancer
Inst. Volume 95, Issue 17 pp. 1336-1343.
11) Natural history of dysplasia of the uterine cervix.
Holowaty P, et al. Jnl Natl Cancer Inst. 1999 Feb 3;
91(3):252-8.
12) A long-term study of women with normal
colposcopy after referral with low-grade cytological
abnormalities. Smith M.C. et al: BJOG. 2006; 113(11):
1321-8.
Italian Journal of
Gynaecology & Obstetrics
March 2017 - Vol. 29 - N. 1 - Quarterly - ISSN 2385 - 0868
Efficacy of TIAGIN® on post-operative reepithelialization in women
subjected to cervical surgery (LEEP or laser cone biopsies): case-control
study
Anna Daniela Iacobone1, Eleonora Petra Preti1, Ailyn Mariela Vidal Urbinati1,
Eugenia Tomás Roldán2
1
2
Preventive Gynaecology Unit, European Institute of Oncology, Milan
CERISMAS Research Centre, Catholic University of Milan
ABSTRACT
Objective: to evaluate the efficacy of post-operative
treatment with TIAGIN® vaginal softgel in the
reepithelialisation of the cervix and the prevention of
the most common post-operative complications.
Methods: a prospective and randomised case-control
study in women who had undergone cervical surgery:
TIAGIN® users for 15 days and non-users. All patients
underwent a clinical examination at baseline and at 30
days. The post-treatment reepithelialisation process
was evaluated by 2 colposcopists. A visual analogue
questionnaire was completed in the second and
fourth week after surgery to assess vaginal bleeding,
leucorrhoea, abdominal pain and impact of pain on
quality of life.
Results: 30 patients were enrolled: 12 as controls and
18 as cases. 5 LEEP (41.77%) and 7 laser cone biopsies
(58.33%) were carried out among controls and 9 LEEP
(50.00%) and 9 laser cone biopsies (50.00%) among cases.
CIN2-3 was detected in more than 70% of patients. No
statistically significant differences were observed in
post-operative complications, with the exception of
the rate of atypical leucorrhoea (66.67% in controls vs
16.67% in cases) (p=0.011). Complete reepithelialisation
was seen in 66.6% of cases and in 8.33% of controls,
respectively (p=0.002).
Conclusion: the post-operative use of TIAGIN® vaginal
softgel leads to rapid cerval reepithelialisation.
SOMMARIO
Obiettivo: efficacia del trattamento post-operatorio di
TIAGIN® softgel vaginali nella riepitelizzazione della
cervice uterina e nella riduzione delle complicanze postoperatorie.
Metodi: studio prospettico randomizzato in pazienti
sottoposti a LEEP/laserconizzazione: pazienti trattate
con TIAGIN® softgel vaginali per 15 giorni e controlli
non trattate. Le pazienti hanno eseguito visita
ginecologica e colposcopia al tempo zero e a 30 giorni. Il
grado di riepitelizzazione cervicale é stato valutato da 2
colposcopisti esperti. Un questionario visuo-analogico è
stato somministrato dopo 2 e 4 settimane dall’intervento
chirurgico per valutare entità del sanguinamento,
leucorrea, intensità del dolore addominale ed impatto
del dolore sulla qualitá di vita.
Risultati: 30 pazienti arruolate di cui 12 nel gruppo
controllo e 18 nei casi. Sono state eseguite: 5 LEEP
(41.77%) e 7 laserconizzazioni (58.33%) nei controlli; 9
LEEP (50.00%) e 9 laserconizzazioni (50.00%) nei casi.
70% delle pazienti ha avuto un istologico CIN2/3. Nel
gruppo dei controlli si è avuta una maggior leucorrea
rispetto ai casi (66.67% vs 16.67%) (p=0.011), mentre la
riepitelizzazione completa si è verificata nel 66.6% del
gruppo dei casi rispetto all’8.33% dei controlli (p=0.002).
Non sono state trovate altre differenze statisticamente
significative nel tasso di complicanze post-operatorie.
Conclusioni: TIAGIN® softgel vaginali nel postoperatorio velocizza la riepitelizzazione della cervice.
Keywords: TIAGIN® vaginal softgel, cervical surgery,
post-operative complications, reepithelialisation
Corresponding to: [email protected]
Copyright 2017, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-63
17
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
INTRODUCTION
18
Wound healing is a multifaceted process
comprising three phases: inflammation,
proliferation and remodelling with the growth of
the epithelium and connective tissue.(1)
The production of cytokines deriving from the
inflammatory processes influences the healing
process, while certain immunological mediators
and bacterial colonisation can delay this process(2).
The early inflammation that occurs as a
physiological response to the tissue damage can
prevent an incipient infection, but prolonged
inflammation can cause cell damage. In fact,
the presence of pathogens produces toxins and
enzymes that protract the inflammatory response
and delay healing, with an increased risk of
complications.(2-3)
The rapid repair of the wound bed is essential
in order to avoid secondary bacterial infection
and thus prevent complications, particularly after
surgery.
Silver-based products have historically been
recommended in wound management because
of their bactericidal properties. However, the
frequent and long-term application of these
topical products produced inflammation and
cosmetic defects. What is more, the advent of
antibiotic therapy considerably reduced the use of
these medications. The arrival of nanotechnology
has allowed to create silver nanoparticles, with
improved solubility and surface properties and,
consequently, fewer side effects.(4)
The innovative patented TIAB® formula creates
a protective film on the vaginal mucosa that
releases nanoparticles of ionic Ag (Ag+) stabilised
with TiO2 (TIAB® System). The silver nanoparticles
have a larger surface area and this increases the
release rate of the individual metal charges,
which are the most soluble and biologically active
part.(5) They also possess multiple antibacterial
mechanisms: they are oxidized and release a silver
charge that damages the cellular membrane of the
pathogenic microorganisms. The ions penetrate
the cytoplasm, prevent the replication of the
DNA, deactivate the respiratory enzymes and
block cellular division until cell lysis occurs. They
also generate free radicals, which have significant
bactericidal properties.(6-8)
TIAGIN ® contains a blend of TIAB® and
hyaluronic acid.
During the inflammatory phase, lowmolecular-weight hyaluronic acid accumulates
in the wound bed, where its main function is to
modulate the action of the inflammatory cells and
the activity of fibroblasts, such as cell migration,
TIAGIN® and reepithelialisation after cervical surgery
cytokine synthesis and microbe phagocytosis.
High-molecular-weight hyaluronic acid, on the
other hand, keeps the wound moist by absorbing
water. During the second phase of tissue damage,
hyaluronic acid acts on the fibrocyte differentiation
mechanisms and the expression of macrophage
metalloelastase. In brief, all the mechanisms
involved in the tissue repair phase involve lowmolecular-weight hyaluronic acid as the principal
player, as it aids the rapid reconstruction of the
healthy tissue.(9-10)
Various clinical studies have been carried
out to evaluate the use of low-molecular-weight
hyaluronic acid in the various fields of medicine,
including gynaecology.(11-12)
A cone biopsy is a surgical procedure used
for the diagnosis and treatment of pre-cancerous
lesions affecting the uterine cervix. Surgical
techniques vary depending on the hospital and the
experience of surgeons. A cold knife cone biopsy
used to be the most common surgical procedure,
but the most widespread technique today is LEEP
(Loop Electrosurgical Excision Procedure), while
specialist sites carry out laser cone biopsies.(13-14)
All these techniques remove part of the uterine
cervix for histopathological analysis. They are
relatively simple procedures and are usually
performed under local anaesthetic.
In literature, there are very few studies about
the immediate and/or subsequent complications
associated with the various techniques described
above. A recent meta-analysis, which compares
LEEP/laser cone biopsy with cold knife cone
biopsy estimates that adverse events affect around
1.1% of women, subdivided into: bleeding (RR
0.226-0.859), infection (RR 0.128-0.089), PID (RR
0.139-0.138) and minor bleeding (RR 0.363-2.450).(15)
On the contrary, a more considerable number
of studies evaluated obstetric outcomes in women
subjected to surgical treatment of the cervix. Cold
knife cone biopsy would seem to be associated
with a higher number of preterm births and/or
PPROM, as laser cone biopsy, compared to LEEP
procedures. The reason of these results is probably
related to the quantity of tissue removed, that
leads to an increased risk of bacterial infections,
PPROM and preterm birth, rather than the
technique itself.(16)
At present, there are no clinical studies
evaluating the efficacy of capsules containing
silver nanoparticles associated with hyaluronic
acid (TIAGIN® vaginal capsules) in women who
have just undergone cervical surgery. Hyaluronic
acid has a positive effect on fibroblast proliferation.
Anna Daniela Iacobone et al.
TIAGIN® and reepithelialisation after cervical surgery
Thanks to its negative charge, it is localised in the
extracellular region, where a hydrophilic network
develops and can carry nutrients and metabolites
to the different cell types by means of a percolation
mechanism. Moreover, the addition of Ag+ NPs
fosters collagen formation and controls its spatial
orientation. Therefore, it is possible to hypotizise
that the scarring and antibacterial action of this
combination (Ag + hyaluronic acid) can reduce
post-surgical repair times and post-operative
complications.
OBJECTIVE
The primary objective of our study was
to evaluate the efficacy of post-operative
treatment with TIAGIN® vaginal capsules in the
reepithelialisation of the cervix and the prevention
of the most common post-operative complications
(abdominal pain, bleeding and atypical vaginal
discharge).
MATERIALS AND METHODS
We carried out a prospective and randomised
case-control study in women who had undergone
cervical surgery in order to compare the reparatory
phenomena and post-operative complications at 2
and 4 weeks after the operation between TIAGIN®
vaginal capsule users and non-users.
All the women who underwent LEEP (Loop
Electrosurgical Excision Procedure) or a laser
cone biopsy at our institute from 11 April 2016
to 31 July 2016 were given the opportunity to
take part in the study. The exclusion criteria
were: pregnancy, congenital or acquired immune
deficiency syndrome, immunosuppressant use,
previous hysterectomy, and/or the use of other
vaginal medications during the week prior to
surgery.
The study was approved by our Institute
Review Board and all the participating subjects
signed an informed consent form.
The study protocol included two enrolment
arms: a group of patients subjected to postoperative treatment with vaginal capsules
containing TIAGIN® for 15 days and a group of
patients who did not take any post-operative
vaginal treatment. The randomisation procedure
was carried out by personnel not involved in the
clinical study, who also assigned the progressive
participation numbers.
All patients underwent a clinical examination,
including a gynaecological visit and a speculum
examination at baseline (at the time of surgery)
and at 30 days. The clinical evaluations were
carried out by gynaecological experts in cervical
disease, certified by the Italian Society of
Colposcopy and Cervicovaginal Pathology, who
assigned a score between 1 and 3 to the posttreatment reepithelialisation process (1: ectocervix
completely reepithelialised, 2: ectocervix covered
in a thin epithelium with areas of immature
metaplasia, 3: ectocervix with persistent areas of
erosion, prone to bleeding), based on a subjective
assessment.
All the enrolled women completed a baseline
questionnaire regarding their socio-demographic
characteristics and obstetric/gynaecological
history and a questionnaire regarding the main
post-operative complications in the second and
fourth week after surgery. The complications
questionnaire used a visual analogue scale as
follows:
√ extent of vaginal bleeding
(slight-moderate-abundant)
√ extent of leucorrhoea (0-10)
√ intensity of abdominal pain (0-10)
√ impact of pain on quality of life (1-5)
STATISTICAL ANALYSIS
Patients’ main characteristics were expressed
as absolute and percentage frequencies.
Post-operative complications and the clinical
evaluation of the reepithelialisation process of
cases and controls were grouped together as
categorical variables and compared with Fisher’s
exact test. P values ≤ 0.05 were considered
statistically significant.
Alla data were analysed using SAS software
(version 9.3).
RESULTS
From April to July 2016, more than 150 cervical
surgery procedures were carried out at our
institute, all on an outpatient and day surgery
basis. A total of 30 patients were enrolled: 12 in the
control group and 18 in the case-study group. The
low percentage of subjects signing up to the study
can be attributed almost entirely to the need to
attend a check-up visit 30 days after the operation,
as many of our patients live over 100 km away
from our hospital.
The main socio-demographic and clinical
19
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
TIAGIN® and reepithelialisation after cervical surgery
characteristics of the study population are
summarized in Table 1 and are comparable in
the two groups. The enrolled patients had a mean
age of 39.26 ± 13.44 and were predominantly
multiparous (56.67%).
As regards to methods of contraception, the use
of birth control pills was prevalent in the control
group (16.67%), while barrier contraception was
predominant in the case group (44.44%).
Table 1.
Main socio-demographic and clinical characteristics of the enrolled population.
TOTAL
(N=30)
CONTROLS
(N=12)
CASES
(N=18)
Mean (SD)
Mean (SD)
Mean (SD)
39.26 (13.44)
41.25 (3.54)
39.94 (14.14)
n (%)
n (%)
n (%)
Nulliparous
13 (43.33)
6 (50.00)
7 (38.89)
Smoker
13 (43.33)
5 (41.66)
8 (44.44)
Oral contraceptives
3 (10.00)
2 (16.67)
1 (5.56)
Condom use
9 (30.00)
1 (8.33)
8 (44.44)
Vaginal infections in the last year
9 (30.00)
3 (25.00)
6 (33.33)
Cystitis in the last years
7 (23.00)
3 (25.00)
4 (22.22)
LEEP
14 (46.67)
5 (41.77)
9 (50.00)
16 (53.33)
7 (58.33)
9 (50.00)
Negative
3 (10.00)
1 (8.33)
2 (11.11)
CIN1
4 (13.00)
2 (16.67)
2 (11.11)
22 (73.33)
9 (75.00)
13 (72.22)
1 (3.33)
0 (0.00)
1 (5.56)
Age (years)
Operation type
Laser cone biopsy
Histology test
CIN 2-3
VAIN3
20
The surgical procedures carried out were as
follows: 5 LEEP (41.77%) and 7 laser cone biopsies
(58.33%) among controls and 9 LEEP (50.00%) and
9 laser cone biopsies (50.00%) among cases.
The histopathological analysis revealed the
presence of CIN2-3 in more than 70% of patients
of both groups.
The clinical evaluation of the post-surgery
cervical reepithelialisation process at 30 days
revealed a statistically significant difference
between the two groups (Figure 1).
Fig. 1
Cervical reepithelialization score
TIAGIN® and reepithelialisation after cervical surgery
Anna Daniela Iacobone et al.
In fact, in 66.6% (12/18) of the women who
used vaginal capsules containing TIAGIN®, the
examining gynaecologists assigned a score of 1,
indicating complete reepithelialisation, which was
only awarded in 8.33% (1/12) of the women who
did not use any local post-surgery treatment. In
addition, 50% (6/12) of the control group showed
areas of erosion prone to bleeding during the postoperative visit (p=0.002).
(Figures 2.1 and 2.2).
Fig. 2.1
Two control patients immediately after the operation and at the
30-day check-up
Fig. 2.2
Two cases patients immediately after the operation and at the 30-day
check-up
As shown in Figure 3 no statistically significant
differences were observed in post-operative
complications between cases and controls, both at
2 and 4 weeks, with the exception of the rate of
atypical leucorrhoea at 2 weeks, which was higher
in the control group (66.67%) compared to the case
group (16.67%) (p=0.011).
Lastly, none of the patients reported severe
abdominal pain or maximum impact of pain on
quality of life.
Fig. 3
Post-operative complications
21
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
CONCLUSIONS
In the light of recent literature, there are no
studies about the use of silver nanoparticles in
combination with hyaluronic acid to reduce the
risk of complications after cervical surgery.
Many methods have been evaluated for the
prevention of severe bleeding after cone biopsies.
Doyle reports the application of a Monsel
solution post-treatment,(17) Kim K. describes a
retrospective study for the use of a fibrin sealant
on the wound bed post-LEEP [18] and Kim JJ.
describes the preventive use of Tachosil®.(19) All
these authors showed that these agents do not
lead to a statistically significant difference in the
prevention of bleeding, except Kim K., which
demonstrates a significant reduction of severe
bleeding (p=0.033, OR - 0.328, 95% CI 0.117-0.917),
despite a consistant impact on costs.(18)
Indeed, the most recent guidelines do not
advise any specific therapeutic agent for the
prevention of severe bleeding.
Our study reflects the results of previous
studies regarding the risk of slight or severe
bleeding, with no statistically significant
difference between TIAGIN® vaginal capsule users
and non-users. However, the number of patients
was limited and there were no episodes of severe
bleeding that required hospitalisation and/or
cervical haemostasis, even in the cases of cone
biopsies with a cone length of > 2 cm.
For what concerns compliance of patients,
none of the case-subjects stopped treatment due to
problems associated with the use of the capsules
22
TIAGIN® and reepithelialisation after cervical surgery
(increased bleeding, blood loss, discomfort or
other), so confirming the good tolerability of the
capsules and their easy application.
The most statistically significant finding
is related to the clinical evaluation, which
demonstrates good and rapid reepithelialisation
in the group of women treated with TIAGIN®
capsules. This result could have a considerable
impact on the risk of infection and chronic
inflammation. We should not forget that,
by reducing the length of the uterine cervix,
cervical surgery can increase the risk of infection
and preterm birth. Previous literature already
showed that the higher risk of preterm birth is a
consequence of modifications of the local vaginal
flora in association with other co-factors.
The rapid repair process in TIAGIN® vaginal
capsule users means that the uterine cervix is
shortly exposed to chronic inflammation and
associated cytotoxic factors. Thereafter, the
bactericidal effect of silver acts as an adjuvant
in this process, restricting bacterial colonisation.
Although not statistically significant in terms of the
immediate complications associated with cervical
surgery, all these factors entail an improved
healing of the uterine cervix and a possible benefit
for subsequent obstetric outcomes.
A long-term follow-up and more clinical
studies evaluating obstetric outcomes are certainly
mandatory to verify whether this kind of support
treatment during the post-surgery phase can lead
to a long-term improvement of quality of life.
TIAGIN® and reepithelialisation after cervical surgery
REFERENCES
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3) Thw comparative efficacy of two antimicrobial
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5) Silver nanoparticles as a new generation of
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disease. Jiang D., Liang J., Noble PW. Physiol Rev 2011
Jan; 91(1):221-64.
11) Diagnosis and treatment of atrophic vaginitis.
Bachmann GA., Nevadunsky NS. Am Fam Physician
Anna Daniela Iacobone et al.
2000 May 15;61(10):3090-6.
12) Effectiveness and safety of vaginal suppositories
for the treatment of the vaginal atrophy in
postmenopausal women: an open, non-controlled
clinical trial. Costantino D., Guaraldi C. Eur Rev Med
Pharmacol Sci 2008Nov-Dec;12(6):411-6.
13) Surgery for cervical intraepithelial neoplasia.
Martin-Hirsch PP, Paraskevaidis E, Bryant A, Dickinson
HO. Cochrane database Syst Rev 2013;12:CD001318.
14) Treatment of cervical intraepithelial neoplasia
using the loop electrosurgical excision procedure.
Wright Jr TC., Cagnon S., Ricart RM., Ferenczy A.
Obstet Gynecol 1992; 79:173-8.
15) Systematic reviews and meta-analyses of benefits
and harms of cryotherapy, LEEP, and cold knife
conization to treat cervical intraepithelial neoplasia.
Santesso N., Mustafa RA., Wiercioch W., Kehar R.,
Gandhi S., Chen Y., Cheung A., Hopkins J., et al.,
International Journal of Gynecology and Obstetrics
2016;132:266-271.
16) The risk of pretermbirth following treatment
for precancerous changes in the cervix: a systematic
review and meta-analysis. Bruinsma FJ, Quinn MA.
BJGO 2011; 118(9);1031-41.
17) Does application of Monsel’s solution after loop
diathermy excision of the transformation zone reduce
post operative discharge? Results of a prospective
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Redman C., Hiller C., Chenoy R., O’Brien S. Br J Obstet
Gynaecol 1992;99:1023-4.
18) Efficacy of fibrin sealant in reducing hemorrhage
after a loop electrosurgical excision procedure. Kim K.,
Park SI., Kim MH., Choi SC., Ryu SY., Lee ED. Gynecol
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19) Efficacy of TachoSil® in preventing hemorrhage
after loop electrosurgical excision procedure. Kim
WY., Lee DH., Kang JH., Song T., Lee KW., Kim KH.
Eur J Obstet Gynecol Reprod Biol 2015 Nov;194:245-8.
23
Italian Journal of
Gynaecology & Obstetrics
March 2017 - Vol. 29 - N. 1 - Quarterly - ISSN 2385 - 0868
Colposcopy and cytology after treatment with TIAB® system and
hyaluronic acid-based vaginal capsules in patients who have undergone
cervical surgery due to an HPV-related disease
Giada Lavitola1, Nicoletta De Rosa1, Ilaria Morra1, Carmine Nappi1, Giuseppe Bifulco1
1
Department of Obstetrics, Gynaecology and Urology, Federico II University Hospital Trust, Naples)
ABSTRACT
Introduction: LEEP (Loop Electrosurgical Excision
Procedure) is the preferred technique for the treatment
of high-grade precancerous cervical lesions (CIN2+).
The post-operative follow-up provides for a colposcopy
and cytology check-up 6 months after treatment. These
examinations are designed to detect the presence of any
residual disease. The surgical wound must have healed
completely at the follow-up in order to obtain conclusive
diagnostic results. This study aims to evaluate the efficacy
of a topical TIAB® system and hyaluronic acid-based
therapy in inducing complete tissue repair.
Materials and methods: 327 patients diagnosed with
CIN2+ who had undergone LEEP were randomised into
two groups. Group 1 (No. 152) received post-operative
treatment with TIAB® system and hyaluronic acid-based
vaginal capsules. Group 2 (No. 175) was the control group
and did not receive any treatment. The patients underwent
a colposcopy and cytology check-up at 1 and 4 months
after treatment.
Results: at 1 month after treatment, the cytology
assessment showed group 1 to have a higher percentage
of satisfactory cytological specimens, a lower percentage of
altered microbial flora and a higher incidence of complete
maturation (p<.001). At the 4-month follow-up, it was
found to have a lower percentage of altered microbial flora
and a higher incidence of complete maturation (p<.001).
The colposcopy carried out at 1 month shows a significantly
higher percentage of inadequate results in group 2 than in
group 1. At 4 months, 74.3% of colposcopies in group 2
showed the presence of immature metaplasia, which was
significantly higher than in group 1 (3.3%; p<.001).
Conclusions: topical treatment with TIAB® system and
hyaluronic acid-based vaginal capsules permits rapid
restoration of the ectocervix following LEEP treatment.
Complete tissue scarring allowed the satisfactory and
adequate execution of the cytology and colposcopy
examinations in 80.3% and 89.5% of cases respectively, at 1
month after follow-up, and a trophic squamous epithelium
at 4 months after treatment.
Keywords: LEEP; colposcopy; cervical intraepithelial
neoplasia; hyaluronic acid; TIAB® system.
Corresponding to: [email protected]
Copyright 2017, Partner-Graf srl, Prato
DOI: 10.14660/2385-0868-64
SOMMARIO
Introduzione: la LEEP (Loop Eletrosurgical Excision
Procedure) è la tecnica di elezione per il trattamento
delle lesioni preneoplastiche del collo uterino di alto
grado (CIN2+). Il follow up post-operatorio prevede un
controllo colposcopico e citologico a distanza di 6 mesi
dal trattamento. Tali indagini hanno come obiettivo di
identificare la presenza di patologia residua. Una completa
guarigione della ferita chirurgica al follow up è necessaria
per ottenere esami diagnostici conclusivi. Obiettivo di
questo studio è di valutare l’efficacia di una terapia topica
a base di TIAB® system e acido Ialuronico nell’induzione di
una completa restituzio ad integrum dei tessuti.
Materiali e metodi: 327 pazienti con diagnosi di CIN2+ e
sottoposte a LEEP sono state randomizzate in due gruppi.
Il gruppo 1 (N= 152) ha eseguito nel post-operatorio una
terapia con capsule vaginali a base di TIAB® system e acido
ialuronico; il gruppo 2 ( N=175) è stato considerato gruppo
di controllo e non ha eseguito alcuna terapia. Le pazienti
hanno quindi eseguito follow up citologico e colposcopico
a 1 e a 4 mesi dal trattamento.
Risultati: a distanza di 1 mese dal trattamento il gruppo
1 ha dimostrato al referto citologico una percentuale
maggiore di preparati citologici soddisfacenti, una più
bassa percentuale di flora microbica alterata ed una più
alta incidenza di maturazione completa (p< .001); al
follow up eseguito al mese 4 viene dimostrata una più
bassa percentuale di flora microbica alterata ed una più
alta incidenza di maturazione completa (p< .001). La
colposcopia eseguita al mese 1 dimostra una percentuale di
referti inadeguati significativamente maggiore nel gruppo
2 che nel gruppo 1. Al mese 4, nel gruppo 2 la percentuale
di colposcopie che rivelano la presenza di metaplasia
immatura è del 74.3 %, significativamente maggiore
rispetto al gruppo 1 (3.3%; p<.001).
Conclusioni: la terapia topica con capsule vaginali a base
di TIAB® system e acido ialuronico consente una rapida
restitutio ad integrum della portio a seguito di trattamento
LEEP. La cicatrizzazione tissutale completa consente
l’esecuzione di citologia e colposcopia soddisfacenti e
adeguate nell’80.3% e nell’89.5% dei casi, rispettivamente,
già ad 1 mese di follow up, ed un epitelio squamoso trofico
a 4 mesi dal trattamento.
25
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
INTRODUCTION
Cervical intraepithelial neoplasia (CIN) are
precursors to cervical cancer. As recommended by
the US ASCCP(1) and Italian SICPCV(2) guidelines,
the preferred treatment for CIN2+ lesions is
excision. LEEP is the most widespread technique
used to treat these lesions.
Women who have undergone treatment for
CIN face a 2-to-5-times higher risk of developing
cervical cancer during their life time compared
to the general population.(3) Because of this, they
must undergo the first cytology check-up with
colposcopy at 6 months after treatment.(4-5)
Surgery aims to remove the abnormal tissue.
Its extent depends on the extent of the lesion
identified during the colposcopy and may vary
between 7 and 25 mm in depth.(5)
The cervix has a high capacity for tissue
regeneration. The data that demonstrates this
derives from studies that have evaluated the
post-partum tissue regeneration capacity of this
region. It is the result of a series of biological
processes that involve proinflammatory factors,
metalloproteinases and proteins involved in the
synthesis of the extracellular matrix.(6-8)
It has been shown that cervical tissue
regenerates itself within 6 months of excisional
surgery. Tissue regeneration is related to the
quantity of tissue excised and exceeds 75% when
the excised tissue accounts for less than 14% of the
length of the cervix.(9)
Silver nanoparticles (AgNPs) have
demonstrated bactericidal, virucidal and
fungicidal activity. The patented TIAB® system
contains titanium dioxide microcrystals with
covalently linked silver ions. (10-11) The TIAB®
system has also shown reepithelialising properties,
inasmuch as it regulates collagen production.(12)
Hyaluronic acid (HA) is one of the main
components in the extracellular matrix and plays
an important role in regulating tissue repair.
During the reepithelialisation process, high
localised concentrations of HA stimulate the
migration and proliferation of fibroblasts and
the formation of granulation tissue, encouraging
the deposit of collagen fibres and stimulating
neoangiogenesis.(13)
This study aims to evaluate whether combined
therapy with the TIAB® system and HA can
accelerate the physiological tissue repair process
in order to permit an early follow-up in patients
who have undergone LEEP.
26
Effect of TIAB® system for tissue healing after LEEP
MATERIALS AND METHODS
From September 2013 to May 2015, all patients
diagnosed with CIN2+ who needed excisional
surgery at the Colposcopy and Cervical Pathology
clinic were enrolled in a randomised prospective
study. The inclusion criteria for enrolment were:
1. A positive histological diagnosis of CIN2+
following punch biopsy, in accordance with
WHO criteria.(14)
2. Aged between 30 and 40 years old.
3. No medical history of systemic disorders
such as: diabetes mellitus, thyroid disorder,
blood clotting disorders.
Patients diagnosed with microinfiltrating or
invasive carcinoma or pregnant patients with
cervical disease were excluded from the study.
After having read and discussed the patient
information sheet and agreed to participate in
the study, all the eligible patients who met the
inclusion criteria were enrolled and underwent
a colposcopy and loop electrosurgical excision
procedure (LEEP) with an RF diathermy loop.
The colposcopy was carried out using the
standard technique: application of a vaginal
speculum, cleaning of the ectocervix with sterile
physiological solution, application of 5% acetic
acid, observation through the colposcope with
a 10x and 40x magnifying lens, subsequent
application of Lugol’s iodine, followed by further
observation. The colposcopic images were
attached to the reports. The reports were written
on the basis of the colposcopy criteria identified by
the IFCPC in 2011.(15)
The surgery involved 4 phases:
1. Colposcopy
2. Radial infiltration with local anaesthetic
(ropivacaine hydrochloride monohydrate 7.5)
of the four quadrants of the ectocervix.
3. Tissue excision in one or two steps depending
on the shape of the ectocervix and the extent of
the lesion.
4. Vaporisation of the wound bed with ball
electrode at a power of 70 Watts, with careful
haemostasis control.
The surgical specimen went sent away on a support
and fixed in formaldehyde 4% (DIAPATH).
The sample was then sent to the Pathological
Anatomy laboratory, where it was washed,
included in paraffin and sectioned. Multiple 4
μm sections for each biopsy sample were stained
with hematoxylin/eosin. The examined samples
were classified in accordance with WHO criteria
as negative, CIN1, CIN2, CIN3/Carcinoma in situ
or microinvasive.(14)
Giada Lavitola et al.
Effect of TIAB® system for tissue healing after LEEP
The patients were then randomised into two
groups: group 1 underwent treatment with TIAB®
and hyaluronic acid-based vaginal capsules
for 10 days a month for 4 months from the day
after the operation. Group 2 did not receive any
pharmacological treatment.
Patients in both groups then underwent a
colposcopy and cytological sampling at 1 and 4
months after the operation.
The cytological sample was taken using the
standard technique: application of a vaginal
speculum, cleansing of the ectocervix with
physiological solution, ectocervical sampling with
an Ayre’s spatula and endocervical sampling with
a Cytobrush. The samples were rubbed on a slide,
fixed with isopropyl alcohol - polyethylene glycols
(GIMAFIX) and sent to the Pathological Anatomy
laboratory. The samples then underwent standard
staining according to the Papanicolaou method,
before being examined.
For the purpose of evaluating ectocervical
reepithelialisation, the cytology reports were
categorised as follows:
1. satisfactory or unsatisfactory for reading
(due to severe phlogosis, presence of red blood
cells that obscured the specimen).
If the sample was inadequate for whatever reason
(e.g. insufficient fixation, air drying artefacts or the
presence of contaminants), the case was excluded
from the study.
2. Presence or absence of altered lactobacillary
microbial flora.
3. The degree of cellular maturation was then
assessed:
a. Grade 1: reparatory metaplasia
b. Grade 2: complete maturation
The presence or absence of epithelial cellular
anomalies was not considered as a classification
criterion.
The colposcopy reports were also graded on the
basis of tissue maturation:
1. Inadequate colposcopy, incomplete scarring
makes diagnosis impossible.
2. Colposcopic picture of acidophilia,
suggestive of immature metaplasia.
3. Normal colposcopic picture of a completely
mature trophic squamous epithelium.
Patients with abnormal changes were excluded
from this study.
STATISTICAL ANALYSIS
SPSS 20.0 (SPSS Inc. Chicago, IL) software
was used for the statistical analysis. The data
distribution was evaluated using the Shapiro
Wilks test. The Wilcoxon test and Student’s t-test
were used to compare the nonparametric and
parametric continuous data between the groups.
The Chi-squared test was used to compare the
categorical data between the groups. The level of
significance for all the tests was set at p<0.05.
RESULTS
Three hundred and fifty-two patients met
the inclusion criteria and were enrolled and
randomised in the study. Of these, 327 patients
completed the first and second colposcopy and
cytology follow-up and were therefore included
in the statistical analysis. 152 patients (group-1)
received post-operative treatment with TIAB®
system and hyaluronic-based vaginal capsules,
while 175 patients did not receive any treatment
(group 2, control). Twenty-five patients were
excluded from the study: 14 patients were lost
during follow-up, 4 patients did not take the
prescribed treatment, 7 patients had positive
colposcopy results at 1 month after treatment.
The patients’ demographic data is summed up in
Table 1.
Table 1
Demographic variables of the two study groups
Group 1
(No.=152)
Group 2
(No.=175)
p value
Age (years)
33.7 ± 2.5
33.6 ± 2.4
NS
Parity (no.)
0.4 [0.3-0.5]
0.3 [0.2-0.4]
NS
Group 1: patients receiving post-operative therapy with the TIAB® system
Group 2: control group Mean ± sd; mean [CI, 95%]
27
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
Effect of TIAB® system for tissue healing after LEEP
Table 2 shows the cytology reports for the
two study groups at 1 month and 4 months after
surgery. A statistically significant difference was
observed between the two study groups as regards
the adequacy of the cytological specimen at the 1
month follow-up. The specimen was unsatisfactory
in 40.6% of the untreated cases (group-2) and
in 19.7% of the treated cases (group-1) (p <.001).
A statistically significant difference was also
demonstrated between the groups in the percentage
of altered microbial flora and the maturation
index at both month 1 and month 4 (table 2), with
a lower microbial alteration percentage and a
higher complete maturation percentage in group
1. As regards the data concerning the colposcopy
(table 2), a statistically significant difference was
observed in the colposcopic picture between the
groups at 1 month and 4 months from surgery.
The percentage of inadequate colposcopic pictures
at the first month of follow-up was 41.7% in the
control group, while it was just 10.5% in the treated
group (Table 3).
Table 2
Cytology reports for the two study groups at 1 month and 4 months
after surgery
Cytology
Time 1
Time 1
Group 1
Group 2
p
Group 1
Group 2
p
(No. = 152)
(No. = 175)
value
(No. = 152)
(No. = 175)
value
Satisfaction
122 (80.3)
104 (59.4)
<.001
144 (94.7)
159 (90.9)
<.001
Unsatisfaction
30 (19.7)
71 (40.6)
8 (5.3)
16 (9.1)
Normal
141 (92.8)
128 (73.1)
145 (95.4)
145 (82.9)
Altered
11 (7.2)
47 (26.9)
7 (4.6)
30 (17.1)
Complete
51 (33.6)
11 (6.3)
150 (98.7)
110 (62.9)
Incomplete
101 (66.4)
164 (93.7)
2 (1.3)
65 (37.1)
Adequacy
Microbial flora
<.001
<.001
Maturation
Index
<.001
<.001
Group 1: patients receiving post-operative therapy with the TIAB® system
Group 2: control group no (%)
Table 3
Colposcopy reports for the two study groups at 1 month and 4
months after surgery
Coldoscopy
28
Time 2
Time 1
Group 1
(No. = 152)
Group 2
(No. = 175)
p value
Group 1
(No. = 152)
Group 2
(No. = 175)
p value
Inadeguate
16 (10.5)
73 (41.7)
<.001
0 (0)
5 (2.9)
<.001
Immature
metaplasia
121 (79.6)
99 (56.6)
5 (3.3)
130 (74.3)
Trophic
original
epithelium
15 (9.9)
3 (1.7)
147 (96.7)
40 (22.9)
Group 1: patients receiving post-operative therapy with the TIAB® system
Group 2: control group no (%)
Effect of TIAB® system for tissue healing after LEEP
DISCUSSION
Our findings demonstrate that combined
topical treatment with TIAB® system and HA
accelerates the cervical healing process in patients
who have undergone LEEP due to CIN2+.
A significant increase was demonstrated in
the percentage of cytology specimens adequate
for examination after just one month of treatment
and the percentage of adequate colposcopies was
also significantly higher in the treated group. In
fact, at 1 month from treatment, just 10.5% of cases
in group 1 presented an inadequate colposcopy
and only 19.7% of cases an inadequate cytological
specimen. At 4 months, group 1 recorded 100%
adequate colposcopies and just 5.3% cytological
samples unsatisfactory for examination.
Spontaneous bleeding, partial cervical
deepithelialisation and excessive inflammatory
infiltrate are the conditions that have the most
effect on misdiagnosis during colposcopy and
cytology.
Treatment with TIAB® system and HA also
reduces the number of cases with altered microbial
flora at both 1 month and 4 months from surgery
and this probably contributes to tissue maturation,
with a positive effect on the cytological specimen.
The cervical squamous epithelium is the first
and most important form of innate immune
response in the genital environment, acting as a
mechanical barrier that protects against attacks
by opportunist pathogens.(16) In the absence of
this barrier and in the presence of favourable
factors such as cervical bleeding as a result of
surgery, which alters the vaginal pH, various
pathogens can reproduce more easily and alter
the normal resident microbiota. The onset of
infection in a region undergoing active cervical
reepithelialisation can delay the scarring process,
interfering with normal cellular maturation
processes.
The antimicrobial and antibacterial power of
the TIAB® system would probably tend to restore
balance to the local microbial flora, preventing
contamination with other microbial forms.
The diagnostic and therapeutic procedure for
CIN lesions does not involve cervical swabs being
taken. The presence of infection is therefore not a
decisive factor when choosing the most opportune
time for treatment. Post-operative therapy with
a drug that has antibacterial and antimycotic
properties can reduce the risk of developing
infections during the post-operative period and
definitively delaying prompt and proper healing.
Giada Lavitola et al.
Wound healing is a complex process,
characterised by angiogenesis, granulation tissue
formation, collagen depositing, epithelialisation
and wound contraction.(17) AgNPs have been
shown to promote cutaneous wound healing by
means of anti-inflammatory activity.(18) What is
more, it has been demonstrated in animals and in
the presence of an excisional wound, that AgNPs
contribute positively to the reepithelialisation
process, boosting fibroblast activation.(19)
Hyaluronic acid also possesses specific
reepithelialising properties, leading to fibroblast
proliferation and constituting a hydrophilic
network at the level of the extracellular matrix
that facilitates the transport of nutrients
and metabolites that encourage faster tissue
regeneration.(13)
Our findings show that topical therapy with
the TIAB® system and HA encourages faster
reepithelialisation and squamous cervical tissue
maturation. At the 4-month follow-up, the group
of treated patients showed a trophic squamous
epithelium in 97% of cases, unlike the untreated
subjects, who presented immature metaplastic
tissue in 74% of cases and completely mature
tissue in just 23% of cases.
In terms of clinical impact, this data suggests
that in patients who require an earlier follow-up
so as to rule out the persistence of the disease,
treatment with the TIAB® system and HA could
provide certain benefits with a lower risk of
uncertain or inadequate cytology and colposcopy
results.
It could therefore be of particular benefit to
immunodeficient patients or those receiving
therapy with immunosuppressants, so that they
can resume therapy that is generally suspended
in the presence of HPV-related disease as soon as
possible, and to patients trying to conceive, so that
they do not have to delay for excessive periods
of time. In fact, while CIN is a condition that can
develop at any age, in the natural history of the
infection and carcinogenesis the peak incidence of
CIN2-3 occurs in women aged between 25 and 35,
a period that coincides with the childbearing age
in western countries.(20)
29
It. J. Gynaecol. Obstet.
2017, 29: N. 1 - Supplement
30
Effect of TIAB® system for tissue healing after LEEP
Fig. 1
Colposcopic picture (a) and cytological picture (b) at 1 month from
excisional surgery in a control group patient (group 2).
a) A large area of deepithelialisation can be observed, with
spontaneous bleeding.
b) The red blood cells obscure the view. Specimen inadequate for
examination.
Fig. 2
Colposcopic picture (a) and cytological picture (b) at 4 month from
excisional surgery in a control group patient (group 2).
a) Treatment outcomes can be observed with a periorificial
metaplastic epithelium.
b) Reactive cellular changes caused by phlogosis. Enlarged nuclei
and perinuclear halos with cytoplasmic vacuolations can be
observed.
Fig. 3
Colposcopic picture (a) and cytological picture (b) at 1 month from
excisional surgery in a group 1 patient
a) Cervical reepithelialisation can be observed with metaplastic
squamous epithelium.
b) Squamous epithelium with typical repair, associated with mild
phlogosis. Enlarged nuclei can be observed with evident
nucleolus. Basophilic cytoplasm.
Fig. 4
Colposcopic picture (a) and cytological picture (b) at 4 months from
excisional surgery in a group 1 patient.
a) Complete reepithelialisation can be observed with a trophic and
mature squamous epithelium.
b) Mature squamous metaplasia
Effect of TIAB® system for tissue healing after LEEP
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