volume 3 number 02 - Prevention and Research

Transcript

International Open Access Journal of Prevention and Research in Medicine
Director Prof. Francesco Tomei
VOLUME 3 NUMBER 02
APR-JUN 2013
www.preventionandresearch.com
Apr-Jun 2013|P&R Scientific|Volume 3|N°2
IN THIS NUMBER
Forcella L, Battisti U, Cortini M, Boscolo P
pag. 60-69
Well-being at work in a center for rehabilitation
Benessere lavorativo in un centro di riabilitazione
pag. 70-83
Andrè JC, Frochot C, Manigat R, Allix F, Tomei F
Decreasing the gap between emerging nanotechnologies and citizen through ethical
considerations and socially responsible research: the example of nano-drugs
Riduzione del gap tra nanotecnologie emergenti e cittadini
attraverso considerazioni etiche e ricerca socialmente
responsabile: l'esempio dei nano-farmaci
Montanari Vergallo G, Frati P, Zaami S, Ciancolini G, Correnti FR, di Luca NM
pag. 84-91
The legislative reform of medical liability in Italy and the
decriminalisation of ordinary negligence: controversial issues
La riforma della responsabilità medica in Italia e la depenalizzazione della colpa lieve:
criticità
Campagnolo L, Massimiani M, Aru C, Palmieri G, Carrino A, Mattei M,
Cecchetti C,Bergamaschi A, Sifrani L, Camaioni A, Magrini A, Bottini M, Pietroiusti A
pag. 92-96
Low embryotoxicity of pegylated single wall carbon nanotubes
Nanotubi di carbonio a parete singola funzionalizzati con catene peg mostrano un basso grado di
embriotossicità
Paganini AM, Guerrieri M, Lezoche G, Balla A, Scoglio D, Quaresima S, Intini G,
Antonica M, Lezoche E
pag. 97-109
Loco-regional endoluminal resection with tem technique versus total mesorectal excision by
laparoscopic in the treatment of rectal cancer T2 after neoadjuvant therapy
Resezione loco-regionale endoluminale con tecnica tem versus total mesorectal excision per via
laparoscopica nel trattamento del cancro del retto T2 dopo terapia neoadiuvante
Capoano R, Tesori MC, Mastroluca E, Lacroce G, Police A, Llange K, Gianfrancesco E,
Donello C, Lombardo F, Salvati B
pag. 110-114
The primary and secondary endometriosis within abdominal wall
Endometriosi primaria e secondaria della parete addominale
D’Ambrosio G, Paganini AM, Guerrieri M, Lezoche G, Balla A, Quaresima S,
Scoglio D, Antonica M, Intini G, Mattei F, Lezoche E
pag. 115-122
Mini-invasive treatment of rectovaginal fistula
Trattamento mini invasivo della fistola retto-vaginale
pag. 123-133
Grimaldi E, Carrano F
The experience of family doctors involved in the “Ambulatorio Med” project at the “F.Spaziani”
hospital, Frosinone: data analysis and perspectives
L’esperienza dei medici di famiglia nell’Ambulatorio Med dell’ospedale “F.Spaziani” di Frosinone:
analisi dei dati e prospettive
Caciari T, Casale T, Sancini A, Frati P, De Sio S, Sinibaldi F, Di Pastena C, Scala B,
Buccisano PFM, Capozzella A, Di Giorgio V, Marchione S, Penna M, Tomei F, Tomei G,
Rosati MV
pag. 134-151
Asbestos and onset of mesothelioma: case report
Amianto ed insorgenza di mesotelioma: case report
Miraglia E, Persechino F, Visconti B, Iacovino C, Calvieri S, Giustini S
pag. 152-162
Sun: friend or enemy?
Sole: amico o nemico?
WELL-BEING AT WORK IN A CENTER FOR REHABILITATION
BENESSERE LAVORATIVO IN UN CENTRO DI RIABILITAZIONE
Forcella L1,2, Battisti U3, Cortini M2, Boscolo P1
1
Departments of Experimental and Clinical Sciences, University “G. D’Annunzio” of Chieti-Pescara, Italy
2
Department of Psychological, Humanistic and Territorial Sciences (DISPUTer) , University
“G. D’Annunzio” of Chieti-Pescara, Italy
3
1
2
INAIL, Abruzzo Region, Italy
Dipartimento di Scienze Cliniche e Sperimentali, Università “G. D’Annunzio” di Chieti-Pescara
Dipartimento di Scienze Psicologiche, Umanistiche e Territoriali,
Università “G. D’Annunzio” di Chieti-Pescara
3
INAIL, Regione Abruzzo
Citation: Forcella L, Battisti U, Cortini M, Boscolo P. Well-being at work in a center for rehabilitation.
Prevent Res 2013; 3 (2): 60-69. Available from: http://www.preventionandresearch.com/ .
Key words: well-being at work, health service staff, job stress, rehabilitation
Parole chiave: benessere lavorativo, staff sanitario, stress lavorativo, riabilitazione
Abstract
Background: The quality of the work environment of nurses is a subject of increasing interest since there is a close link
between the quality of care and patient satisfaction. Surveys on the characteristics of hospitals in Europe, United States
and Asia demonstrated that the quality of organizational behaviour influenced emotional exhaustion and the intention to
change jobs in nurses. With regard to this, we performed a survey on the health service staff, at risk of occupational
stress, in a center for rehabilitation located in Abruzzo (Italy).
Methods: The first step of the investigation was to identify homogenous groups of workers considering their duties in
relation to job stress. We investigated all the health service staff, the office-workers and the blue collar workers (117
women and 58 men); 85% of them were in a stable job. We used anonymous questionnaires to evaluate the perception
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of anxiety, job stress and symptoms. State trait anxiety inventory (STAI) was used in scale 1, to measure state-anxiety
as a temporary and varying condition, and in scale 2, to monitor trait-anxiety, as a relatively fixed tendency of the
personality. Occupational stress was determined by the Italian version of the Karasek Job Content Questionnaire,
composed of 49 items, determining decision latitude (DL), job demand (JD) job strain (JD/DL), social support and job
insecurity. The perception of symptoms was also evaluated by a 10 item questionnaire.
Results: The levels of anxiety and job insecurity of all the groups of workers were within the normal range.
Physiotherapists and professional nurses showed rather higher anxiety, elevated job demand (JD), rather lower decision
latitude and higher job strain (“job strain” = JD/DL). The health care assistants showed lower JD and DL similar to that
of the professional nurses. The social assistants, teachers and logopedics showed rather low JD and rather elevated DL.
Physicians had low values of anxiety, job demand and job strain, high DL and low perception of symptoms. The job
stress of the blue collar workers of the hospital was similar to that of the professional nurses and physiotherapists. The
perception of symptoms in all the sanitary staff was highly correlated with levels of anxiety and job strain.
Conclusions: The low levels of anxiety and job insecurity of the health service staff show that, in this center, the work
environment was of good quality. However, this study also indicates that in centers for rehabilitation and treatment of
chronic diseases, the levels of occupational stress of physiotherapists and professional nurses are higher than those of
the other groups of health
service staff (social assistants, teachers and logopedics). This investigation thus
demonstrates that it necessary to improve the work environment of physiotherapists and professional nurses (fewer than
the number required for the health care of the increasingly ageing population), also in order to avoid them leaving their
jobs and therefore maintaining workforce stability.
Abstract
Introduzione: Il benessere organizzativo in ambito socio-sanitario costituisce un tema di particolare interesse in quanto
vi sono stretti rapporti tra la qualità dei processi organizzativi e quella dell’assistenza erogata. Studi eseguiti in paesi
Europei, negli Stati Uniti ed in Asia hanno dimostrato che gli operatori in strutture sanitarie possono presentare
insoddisfazione lavorativa e “burnout” con abbandono anticipato della professione. Per questo motivo abbiamo condotto
un’indagine sul personale di
una struttura riabilitativa Abruzzese che poteva essere soggetto a rischio di stress
lavorativo.
Metodi: Abbiamo eseguito l’indagine su 175 lavoratori (117 donne e 58 uomini) con differenti mansioni; l’85 % dei
lavoratori era con contratto a tempo indeterminato. Il primo momento di analisi ha identificato gruppi omogenei di
lavoratori, con caratteristiche comuni di rischio organizzativo. Si è ricorso a metodi di indagine con questionari per
valutare la percezione soggettiva dell’ansia, dello stress lavoro-correlato e della sintomatologia. Lo STAI 1 e lo STAI 2
sono stati utilizzati per determinare l’ansia di stato e di tratto. Lo stress lavorativo è stato determinato con una versione
Italiana del test di Karasek Job Content Questionnare (JCQ), composta di 46 item, per determinare la “decision latitude”
(DL), la “job demand”, il “job strain (JD/DL), il supporto sociale e la “job insecurity”. E’ stata valutata anche la
percezione della sintomatologia con un questionario di 10 item.
Risultati: I livelli di ansietà e di “job insecurity” di tutti i gruppi esaminati erano nel “range” dei valori normali. I
fisioterapisti e gli infermieri presentavano livelli di ansietà più elevati, domanda lavorativa elevata (JD) , discreti livelli di
capacità decisionale (DL) e, nel complesso, livelli elevati di “job strain” (“job strain” = JD/DL). Gli ausiliari presentavano
JD lievemente inferiore e DL simile a quella degli infermieri. Gli assistenti sociali, gli educatori ed i logopedisti
presentavano JD non elevata e buona DL. I medici avevano livelli di ansietà non elevati, JD abbastanza alto con elevata
DL e bassa percezione dei sintomi soggettivi. I “blue collars” presentavano livelli di “job strain” analoghi a quelli degli
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infermieri e dei fisioterapisti. La percezione dei sintomi era correlata in modo altamente significativo con i valori di
ansietà e di stress lavorativo.
Conclusioni: Nel complesso possiamo definire che il “clima lavorativo” dello “staff” di questo centro sanitario era di
buona qualità con percezione di ansietà e di timore di perdere il lavoro non elevata. Tuttavia i livelli di stress lavorativo
dei fisioterapisti e degli infermieri professionali erano più alti di quelli delle altre figure dello staff sanitario (medici,
assistenti sociali, educatori e logopedisti). La nostra indagine indica pertanto che, nelle strutture socio-sanitarie e
riabilitative, sono necessari interventi sulla organizzazione del lavoro dei fisioterapisti e degli infermieri professionali
(carenti di numero in rapporto alle richieste della popolazione che sta invecchiando) anche al fine di impedire un
abbandono anticipato della professione.
Background
In work environments, along with the risks related to the traditional occupational diseases, there are psychological risks
which may induce disorders affecting the health of workers. The psycho-social factors are a problem of increasing
importance since they may reduce both the quality of life style and the efficiency of industries and services, not only in
Italy but also in all European Countries. With regard to this, it has been demonstrated that the psycho-social well-being
of workers in hospitals and health care centers is closely related to the quality of care and patient satisfaction with the
treatment received (1,2).
A pilot study on the health service staff of the University of Brescia correlated objective and subjective parameters of
occupational stress and burnout (3); the results showed a significant correlation between 6 objective indexes (regarding
inefficiency of the organization) of job strain and subjective parameters determined by an Italian version of the Job
Content Questionnare (JCQ) (4,5), the Maslach Burnout Inventory (MBI) (6) and the State-Trait Anxiety Inventory
(STAI) (7).
Night-shift work is one of the main risks for health service staff since it induces circadian disruption of physiological
neuroendocrine and immune rhythms. It may either reduce the attention in work activities with higher risks of mistakes
and accidents or enhance the onset and progression of organic diseases (8). 220 shift workers and 422 day-time
workers in an Italian hospital were investigated to detect any relationship of shift work with subclinical autoimmune
hypothyroidism (9). Subclinical autoimmune hypothyroidism was seen in 8% shift workers, compared to 4% day-time
workers, and elevated titers of anti-peroxidase thyroid (TPO) autoantibody in 14% shift workers, compared to 9% in
day-time workers.
A survey was performed on general acute care hospitals in 12 European countries and in the United States to determine
whether good organization can affect patient care and workforce stability. The results showed that the quality of
organizational behavior influenced the level of satisfaction for the treatment in patients and emotional exhaustion and
the intention to change jobs in nurses (1). The results, evidencing defects of the organization in every country, also
evidenced that cost for improving the work environment seemed to be relatively low.
A cross-cultural and longitudinal study (Nurses Early Exit Study: NEXT) on the working conditions, health and wellbeing
of nurses was carried out. Data on 6,469 nurses working in hospitals in seven European Countries showed that 8.24% of
nurses had newly developed intentions to leave during the follow-up. High effort-reward imbalance predicted an
elevated risk of intention to leave the profession; reward frustration showed the strongest explanatory reason. Findings
were similar in the majority of countries, with lower association between job stress and intention to leave in Netherlands
and in Slovakia (11). The differences among countries are likely justified by cultural, socioeconomic and organizational
variety. With regard to this, it was shown that Italy was a country with relatively lower expenses for nurses (12).
Investigations on the health service staff in northern Italy highlighted elevated frequency of subjects with poor working
capacity, symptoms of chronic fatigue, dissatisfaction with the job and sleep disturbances. These effects increased with
age and were more evident in females because of the difficulty to balance home and job activities and periods of lack of
sleep (13).
In this study we used the “Karasek’s Job Content Questionnaire” which has previously proven to be a useful instrument
in determining job strain in a large group of Italian employees (14), by the staff of a university (10,15), by a group of
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teachers (16), by workers in a clothing industry (17) and by health service staff (3). Today there are different types of
health services for the treatment of acute and chronic diseases and rehabilitation. The role of the centers for
rehabilitation and the treatment of chronic diseases, a part of which also have day hospitals, is increasing because the
population is continuously ageing. Our investigation was performed in these centers of Central Italy; in particular, we
investigated the wellbeing at work of physiotherapists, professional nurses, and social assistants, who were fewer than
the number required in these centers.
Methods
The investigation was carried out in a private clinic for rehabilitation and care of chronic diseases. This health center
(“San Francesco d’Assisi” located in Vasto, near the Adriatic sea) started its activity in 1965 by taking care of young
people with mental diseases. In the following years, it became a center for rehabilitation and treatment of all physical,
sensorial and mental diseases with different ways of health care, including those with periodic or permanent stays in
hospital or hospital and outpatient assistance. The consideration for the activity of this center as well as the level of
patient satisfaction for the treatment received was relatively high. This is in agreement with the percentage of voluntary
collaboration of its health service staff in this research (about 95%) .
Participation in the research was voluntary and, prior to inclusion, all subjects gave their informed consent. The study
protocol was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its
later amendments and was approved by the ethics committee of the University of Chieti-Pescara.
We evaluated the type of sanitary staff taking into consideration the type of work activities and duties. 175 workers
were recruited (117 men: 66.9 %) and (58 men: 33.1 %); only one worker was not of Italian nationality; the age
ranged between 20 and 60 years. Only 6 recruited subjects were not investigated, The health service staff was
composed of physiotherapists, professional nurses, health care assistants, social assistants, teachers and logopedics as
well as physicians; a small group of office-workers and blue collar workers of the same health centers were included as
controls in the study (table 1). Sociodemographic characteristics of the study population are shown in table 2.
Table 1 - Number of male and female workers
Women
Men
Total
Total
Physioterapists
31
11
number
%
42
24
Professional nurses
16
5
21
12
Health care assistants
39
18
57
32.6
19
13
32
18.3
Physicians
5
4
9
5.1
Blue collars
5
1
6
3.4
Office-workers
4
4
8
4.6
Total
117
58
175
100
Social
assistants,
teachers
and
logopedics
63
Table 2 - Age, professional characteristics, education level and smoking habits of the study population
Age
(years)
Physio-terapists
Profess. Nurses
Social ass., teachers,
logopedics
Physicians
Blue collars
Office-workers
Total
44.5±5.
7
41.4±8.
6
44.4±7.
5
45.8±7.
3
49.2±3.
6
55.5±4.
5
50.4±4.
1
45.2±7.
This job
work
time
(years)
17.0±7.
9
13.0±8.
6
14.3±7.
8
19.1±7.
3
14.0±9.
9
17.6±6.
2
25.5±2.
9
16.4±8.
Total
work
time
(years)
20.3±5.
2
17.5±8.
6
21.6±7.
6
21.5±6.
5
17.5±8.
6
17.5±8.
6
26.8±5.
3
21.1±7.
3
1
1
Education level (%)
Secon Secon Degre
d
d
e
low
High
0
7
93
Permanent
contract
(%)
7
Smoke
r
(%)
17
6
38
56
5
28
52
46
2
23
37
6
68
26
12
31
0
0
9/9
3/9
0
5/6
1/6
0
0
1/6
0
4/8
4/8
0
3/8
22
37
41
15
27
Values are means ± S.D.
The office-workers and the blue collars were slightly older, while the physicians were the oldest of the sanitary staff.
Mean overall working life ranged from 17.5 to 26.8 years , while mean working life in the health center of Vasto ranged
from 13.0 to 25.5 years. The working life of the office-workers was the longest, while the working life of the physicians,
professional nurses and health care assistants in the center, was shorter than that of the other groups. 85% of the
recruited subjects had permanent work contracts, 28.5 % were smokers. In particular the group of the health care
assistants had higher % of smokers compared to the group of physicians.
The level of education of the physiotherapists was higher (almost all with degrees) than that of the professional nurses
(50 % with degrees). About 50% of health care assistants and 68% of social assistants, teachers and logopedics had a
high school diploma.
The study was carried out as an anonymous survey using standardized questionnaires; the recruited subjects compiled
the questionnaires in a quiet room.
The state-trait-anxiety inventory (STAI) was used in Scale 1, to measure state-anxiety as a temporary and varying
condition, and in Scale 2, to monitor trait-anxiety, as a relatively fixed tendency of the personality (7).
Occupational stress was determined by the Italian version of the Karasek Job Content Questionnaire (JCQ) composed of
49 items: 9 items determined the decision latitude (skill decision + decision authority) (DL), 8 items determined the
macro level decision authority, 1 item (skill level) for skill underutilization, 14 determined job demand (JD), 12 social
support (SS) and 6 job insecurity (JI). Job strain (JS) was determined by the ratio JD:DL (4,5). The relationship between
JD and DL gave four work conditions characterized by: “high strain” with high JD and low DL; “passive strain”, with low
JD and DL; “active strain”, with high JD and DL; “low strain”, with low JD and high DL.
Perception of subjective symptoms was determined by the Italian version of Somatization scale of Symptom Checklist
SCL-90 (18) that consists of 12 items These items assess the occurrence of several physical symptoms (e.g., headache,
vomiting) in the previous week.
All statistical analyses were performed using SPSS® software 11.0 (SPSS Inc, Chicago, IL, USA). In particular the
multiple comparisons/post hoc tests ” (into the ANOVA) for the analysis of significant differences among groups was
64
utilized, while the Spearman rho correlation coefficient was applied to evaluate the correlation between quantitative
variables such as STAI 1 and STAI 2, DL, JD, JI, SS.
Results
The physiotherapists showed a more elevated perception of trait (STAI 1) and state anxiety (STAI 2) and of subjective
symptoms than that of the other groups of workers (table 3).
Table 3 - Perceptions of anxiety and subjective symptoms of the study population
STAI 1
STAI 2
Subjective
symptoms
Physioterapists
38.7±9.1*
39.6±9.6*
10.9±9.5**
Professional nurses
38.8±8.3*
35.7±9.1
10.0±6.7**
34.9±7.4
35.9±7.6
8.9±6.6
Social assistants, teachers, logopedics
37.2±9.5
34.1±8.9
7.1±6.3
Physicians
35.3±5.7
33.0±4.2
3.3±3.7
Blue collars
36.0±9.8
36±2.7
9.5±11.0*
Office-workers
30.5±6.8
36.1±7.1
7.6±9.7
Total
36.5±8.5
36.3±8.4
8.8±7.7
Multiple comparisons/post hoc tests ”
(into the ANOVA).
Statistical significant difference among the groups:
*p<0.05;**p<0.001
Professional nurses also showed a more elevated perception of trait anxiety (STAI 1) and of subjective symptoms, while
that of the state anxiety (STAI 2) was within the normal range.
The job demand” (JD) of the physiotherapists, professional nurses and health care assistants was high, while their
decision latitude (DL) was rather low; therefore the job strain(JD/DL) was rather elevated, similar to that of the blue
collars (table 4).
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Table 4 - Perception of decision latitude (DL), job demand (JD), social support
(SS), job security (JI), job strain
(JD/DL, JS) of the study population.
Job demand
(JD)
Physioterapists
Professional nurses
Social assistants, teachers,
logopedics
Physicians
37.5±6.1**
39.2±5.3**
35.8±5.0**
32.6±4.4
Decision
Latitude
(DL)
64.3±9.4**
65.2±7.1**
64.9±7.1**
69.0±5.7
30.1±3.2
74.9±6.6
4.1±0.4
18.9±2.6
13.8±2.5
Blue collars
Office-workers
38.5±6.5**
32.9±3.5
64.0±6.6**
69.7±9.8
6.1±1.7**
4.8±0.6
23.2±0.7
22.6±1.8
10.5±1.6
12.4±2.0
35.7±5.6
66.3±8.1
5.5±1.4
21.3±3.8
13.4±2.6
Total
Job strain
(JD/DL)
x 102
6.0±1.2**
6.1±1.0**
5.6±0.6**
4.8±0.9
Social
support
Job security
19.9±3.9
20.4±4.7
22.6±3.5
21.1±3.8
13.4±2.2
13.1±2.8
13.6±3.0
13.8±2.5
Multiple comparisons/post hoc tests ” (into the ANOVA). Statistical significant difference among the groups:
*p<0.05;**p<0.001
Social assistants, teachers and logopedics (as well the office-workers) presented low JD and DL rather high with the “job
strain” (JD/DL) reduced. This was even more reduced in the physicians (table 4).
The social support, slightly lower in the physiotherapists and in the physicians, as well as the job security, did not
present significant differences among all the examined groups (table 4).
The relationship between JD and DL gave four work conditions characterized by: “high strain” with high JD and low DL;
“passive strain”, with low JD and DL; “active strain”, with high JD and DL; “low strain”, with low JD and high DL.
“High strain” (low and right on figure 1), with high JD and low DL, includes physiotherapists, blue collars, professional
nurses (with levels near to those of the “active strain”) and health care assistants
(with levels near to those of the
“passive strain”).
“Active strain” (high and right on figure 1), with high JD DL, includes professional nurses (with levels near to those of
the “high strain”).
“Passive strain” (low and left on figure 1), with low JD DL, includes professional nurses (with levels in common with to
those of the “high strain”) near the interception of the straight lines which divides the 4 working conditions.
“Low strain” (high and right on figure 1), with high JD and low DL, includes health care assistants, social assistants,
teachers and logopedics as well as physicians.
STAI 1 and STAI 2, job demand (JD) and “job strain” were correlated with high statistical significance (p<0.001) (table
5) with the subjective symptoms. JD was highly negatively correlated (p<0.001) with DL , and with lower statistical
significance with STAI 1 and 2.
There were positive correlations (p<0.01) between DL and social support, while there were negative correlations
between DL and “job insecurity”. “Job insecurity” was positively correlated with job strain.
Table 5 also reports other positive or negative correlations between the parameters of anxiety, occupational stress and
perception of symptoms.
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Figure 1 - “Job strain (”Job demand/decision latitude”) of groups of workers with different tasks:“high strain” low and
right; “low strain” (low and left); “active strain” (high and right); “passive strain”(high and left).
76
74
72
70
68
66
64
62
25
30
35
40
45
professional nurses
health care assistants
physioterapists
social assistants‐teachers‐logopedics
office‐workers
blue collars
physicians
median
Table 5 - Linear significant statistical correlations among STAI 1, STAI 2, job strain social support and subjective
symptoms of 175 workers
STAI 2
STAI 1
STAI 2
Job demand
(JD)
Decision
Latitude
(DL)
Job strain
(JD/DL)
Social
Support
Job
Insecurity
0.561***
Job
demand
(JD)
0.177*
0.209**
Decision
Latitude
(DL)
-0.204**
-0.323**
-0.365***
Job
strain
(JD/DL)
0.235**
0.298**
Social
support
Job
insecurity
Symptoms
-0.289**
-0.156*
-0.328**
0.155*
0.137
0.158*
0.426***
0.409***
0.401***
0.277**
-0.173*
-0.335**
-0.359***
0.212**
0.460***
-0.251**
-0.296**
0.144
Statistical significance: *p<0.05; ** p<0.01; ***p<0.001
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Conclusions
Work activity in health care services has specific targets since the demands of the organizations involve the needs of the
patients, which for definition, have to cope with unexpected situations; the workers have therefore to establish a specific
relationship with the patients to help them to understand and adequately manage their own problems. The main aim of
this research was to involve the health service staff of the centers of rehabilitation and health care in order to create a
collaborative environment able to reduce and manage job stress; the collaboration of the recruited subjects consisted in
representing the personal work condition, the aspects of the organization and the personal perceptions of previous
experiences in health care.
The analysis of the work risks may be a tool to suggest, apply and experiment measures for improving the general
organizational, including managerial, support for nursing, doctor-nurse relationships and promotion of care quality. The
main characteristics of the management are demand, control, support, relations, and changes with regard to this, for
any problem which arises, the worker has to receive from the management responses aimed at the solution of his/her
problem.
In Central Italy, and in particular in the Abruzzo region, the quality of life is high since the role of the family and social
traditions are still present. Also for this reason, as well as for the stability of employment (mean working life in the
health center ranged from 13 to 25 years), the levels of anxiety, social support and job insecurity of all the groups of
recruited subjects were (with some differences) within the normal range.
This investigation demonstrates that the level of job strain of the workers in the centers of rehabilitation and health care
depends on the professional activity; the professional role is also related to the education level and lifestyle (including
smoking habits).
Almost all the physiotherapists had a university degree and a stable employment; they showed slightly elevated state
and trait anxiety, high job demand (JD) and rather elevated job strain, rather low decision latitude (DL) and rather high
perception of subjective symptoms. In this group women smoked much more than men.
About half of the professional nurses had a university degree and about half of them had stable employment; they
presented a state of anxiety slightly elevated, high job demand (JD) and rather elevated job strain, low decisional
latitude (DL) and a rather high perception of subjective symptoms.
About half of the health care assistants had a high school diploma; about 70% had stable employment; they did not
show high levels of anxiety, while they presented high job demand (JD) and rather elevated job strain (JD/DL); the DL
was not elevated.
Most of the social assistants, teachers and logopedics had a high school diploma; ; about 70% had a stable
employment; their perception of anxiety and of subjective symptoms was in the normal range as well as JD, DL and job
strain.
The physicians showed low levels of anxiety and perception of symptoms, rather elevated JD with rather high DL, with
levels of job strain in the normal range; the percentage of smokers was very low.
This investigation demonstrates that the perception of symptoms in all the health service staff was highly correlated with
levels of anxiety and job strain which is in agreement with the results of previous studies on office-workers, teachers
and blue collar workers (10,16,17).
In conclusion, this investigation demonstrates that in the rehabilitation and health care centers the occupational strain of
physiotherapists, professional nurses and health care assistants is higher than that of physicians, social assistants and
logopedics. As previously reported, in different countries of Europe, in the United States and in Japan (Kanai-Pak et al.
2008, Hasselborn et al. 2008, Li et al. 2011, Aiken et al. 2012) there is intention of anticipating leaving the current
position by qualified nurses, because of reward frustration and/or high level of job demand with low task control. This
condition may be more evident in the health service qualified staff who take care of elderly patients or those with
chronic diseases, while there is an increased demand for these workers because of the continual ageing of the
population. Improvement of the organizational behavior for the nurse and physiotherapist workforce in the centers for
rehabilitation and health care (where most of the patients in treatment are elderly or have chronic diseases) is
particularly needed. With regard to this, improvement of the hospital work environment for this health service staff, by
improving the managerial behavior, can be a relatively low cost strategy.
68
References
1. Aiken LH, Sermeus W, Van den Heeden K, et al. Patient safety, satisfaction, and quality of hospital care: cross
sectional surveys of nurses and patients in 12 countries in Europe and the United States. BMJ 2012; 344: e1717.
2. Kanai-Pak, Aiken LH, Sloane DM, Poghosyan L. Poor work environments and nurse inexperience are associated with
bornout, job dissatisfaction and quality deficits in Japanese hospitals. J Clin Nurs. 2008; 17:3324-3329.
3. Lucchini R, Facco P, Tromboni E, et al. Lo stress index, proposta di un metodo per la valutazione da stress e burnout
in ambienti sanitari. G Ital Med Lav Erg 2003; 25 s:134-136.
4. Karasek RA, Brisson C, Kawakami N, et al. The Job Content Questionnaire (JCQ). An instrument for Internationally
Comparative Assessments for Internationally Comparative Assessments of Psychosocial Job Characteristics. J Occup
Health Psychol 1998; 3:322-355.
5. Baldasseroni A, Camerino D, Cenni P, et al. La valutazione dei fattori psicosociali – Il Job Content Questionnaire.
Fogli d’Informazione 2001; 3:20-32.
6. Maslach C. Maslach Burnout Inventory, Organizzazioni speciali, Firenze, 1994.
7. Spielberger CD. Inventario per l’Ansia di Stato e di Tratto (versione italiana). O.S. Organizzazioni Speciali,
Firenze, 1989.
8. Costa G. Problematiche del lavoro a turni in ospedale. G Ital Med Lav Erg 2010; 32(3):343-346.
9. Magrini A, Pietroiusti A, Coppeta L, et al. Shift work and autoimmune thyroid disorders. Int J Immunopathol
Pharmacol 2006; 19(4s):31-36.
10. Boscolo P, Di Donato A, Di Giampaolo L, et al. Reduced blood natural killer cytotoxic activity in men working in a
university with occupational stress and job insecurity. Int Archives of Occupational and Environmental Health 2009;
82:787-794.
11. Li J, Galatsch M, Siegrist J, et al. Reward frustration at Work and intention to leave the nursing—prospective results
from the European longitudinal NEXT study. European NEXT Study group. Int J Nurs Stud 2011; 48:628-635.
12. Alessio L, Bonfiglioli R, Buselli R, et al. Aggiornamenti in tema di tutela della salute occupazionale dei lavoratori
della sanità. Atti 71° Convegno SIMLII, G Ital Med Lav Erg 2008; 30:228-237.
13. Camerino D, Sandri M, Conway P, et al. Ruolo dei fattori “genere” ed “età” nella valutazione del rischio psicosociale e
negli interventi di prevenzione del personale ospedaliero. G Ital Med Lav Erg 2010; 32:337-342.
14. Ferrario M, Cecchino C, Chiodini P, et al. Realibility of the Karasek scale in the assessment of perceived occupational
stress and gender-related differences in scores. The SEMM study. G Ital Med Lav Erg 2003; 25:2004-2005.
15. Forcella L, Di Donato A, Di Giampaolo L, et al. Occupational stress and job insecurity may reduce the immune NK
response in men working in a university. Boundaryless Careers and Organizational Wellbeing, Ed. M. Cortini, G.
Tanucci and Palgrave Macmillan E, Part II Occupational Well being, DA 121-131, January 2011.
16. Forcella L, Di Donato A, Reversi S, et al. Occupational stress, job insecurity and perception of the health status in
Italian teachers with stable or temporary employment. J Biol Regul Homeost Agents 2009, 23:85-93.
17. Forcella L, Bonfiglioli R, Cutilli P, et al. Analysis of occupational stress in a high fashion clothing factory with upper
limb biomechanical overload. Int Arch Occup Environ Health 2012; 85:527-535.
18. Violani C, Cariani D, Floresta A. Uno strumento per l’autovalutazione del disagio psicologico. In: Mamone P (ed) Atti
del I congresso Italiano di Psicologia della Salute. Edizioni Kappa, SCL-90 Roma,1999.
Corresponding Author: Paolo Boscolo
Consultant of the University G. D’annunzio of Chieti-Pescara, Italy
e-mail: [email protected]
Autore di riferimento: Paolo Boscolo
Consulente dell’Università G. D’annunzio di Chieti-Pescara
69
Decreasing the gap between emerging nanotechnologies and
citizen through ethical considerations and socially responsible research: the example of nano-drugs
DECREASING
THE
NANOTECHNOLOGIES
GAP
AND
BETWEEN
CITIZEN
EMERGING
THROUGH
ETHICAL
CONSIDERATIONS AND SOCIALLY RESPONSIBLE RESEARCH:
THE EXAMPLE OF NANO-DRUGS
RIDUZIONE DEL GAP TRA NANOTECNOLOGIE EMERGENTI E CITTADINI
ATTRAVERSO CONSIDERAZIONI ETICHE E RICERCA SOCIALMENTE
RESPONSABILE: L'ESEMPIO DEI NANO-FARMACI
Andrè JC1,2, Frochot C1, Manigat R3, Allix F1, Tomei F4
1
LRGP-UPR 3349 CNRS, ENSIC-UdL 1, rue Grandville F54000 Nancy
2
INSIS-CNRS, 3, rue Michel Ange F75016 Paris
3
Ministère du travail, de l’emploi et de la santé, 14 avenue Duquesne, 75007 Paris
4
Department of Anatomy, Histology, Medical-Legal and Orthopaedics, Unit of Occupational Medicine,
“Sapienza" University of Rome, Italy
1
2
3
Ministère du travail, de l’emploi et de la santé, 14 avenue Duquesne, 75007 Paris
4
Dipartimento di Anatomia, Istologia, Medicina Legale e Ortopedia, Unità di Medicina del Lavoro,
“Sapienza” Università di Roma
Citation: Andrè JC, Frochot C, Manigat R, Allix F, Tomei F. Decreasing the gap between emerging nanotechnologies and
citizen through ethical considerations and socially responsible research: the example of nano-drugs.
Prevent Res 2013; 3 (2): 70-83. Available from: http://www.preventionandresearch.com/
Key words: responsible research, risks, ethics, precautionary principle, nano-drugs
Parole chiave: ricerca responsabile, rischi, etica, principio precauzionale, nano-farmaci
70
Abstract
Decisions about the use of science are "existential" to the extent that they concern human well-being, that is, how
people think, develop, act -- how they live. Scientists working within their own disciplines tend to depend on paradigms
and these usually entail mandatory sets of rigid norms. These permit serious and deep pursuit of knowledge but by
themselves don't respond to, let alone overcome, gaps that open between scientific research itself and demands or
needs for public determination of the social applications of research. Researchers must often cope with heavy time
pressures for the financing and the publication of their work. This tends to minimize interdisciplinary efforts and confirm
the priorities of decision-makers who provide financing. The matter is complicated by increasing demands from the public
that scientists factor into their efforts important ethical questions concerning social, economic and political matters. This
makes the requisite tools interdisciplinary and there is a general absence of agreed-on rules for their development and
use. Recent fascination with nanotechnologies as keys to scientific progress suggests the possibility of crafting
appropriate priorities that are not always dependent on calculations of profit. A variety of risks -- ethical, health,
environmental -- arise at the beginning of a project and they bring complexity and interdependence throughout the
effort. Again: these entail social and not solely scientific issues and they cannot be glossed over. This paper aims to
press scientists to consider and reflect on the possible future uses of their accomplishments (in terms of ethics and risks
or hazards for Humans and the environment). It proposes certain humbleness on their part together with a principle of
"Socially Responsible Research" when, for example, applying new nano-drugs in cancer therapy (including limits of
perception of possible problems of researchers and few modest action proposals for a social progress).
Abstract
Le decisioni circa l'uso della scienza sono "esistenziali" nella misura in cui esse riguardano il benessere umano, che è,
come la gente pensa, sviluppo, atto -- come vivono. Gli scienziati che lavorano nelle proprie discipline tendono a
dipendere da paradigmi e questi di solito comportano l’uso di inderogabili e rigide norme. Queste permettono una ricerca
della conoscenza seria e profonda, ma di per sé non rispondono, e non superano, le lacune tra la ricerca scientifica
stessa e le richieste o le necessità necessarie per l’applicazione sociale della ricerca scientifica. I ricercatori devono
spesso far fronte a pesanti pressioni per ottenere i finanziamenti e la pubblicazione dei loro lavori. Ciò tende a ridurre al
minimo lo sforzo interdisciplinare e a confermare le priorità dei decisori che forniscono i finanziamenti. Inoltre la
questione è complicata dalla crescente richiesta da parte della società che vuole gli scienziati attivi nell’includere nei loro
sforzi le importanti questioni etiche riguardanti questioni sociali, economiche e politiche. Il tutto rende indispensabile lo
strumento interdisciplinare ed evidenzia la generale mancanza di accordo sulle norme per il loro sviluppo e utilizzo. Il
recente fascino che individua le nanotecnologie come chiavi per il progresso scientifico suggerisce la possibilità di
lavorare con priorità che non sono sempre dipendenti da calcoli basati sul profitto. Una varietà di rischi -- etici, sanitari,
ambientali -- insorgono all'inizio di un progetto e portano con sé complessità e interdipendenza durante tutto l’impegno.
Ancora una volta: queste comportano questioni sociali e non esclusivamente scientifiche, il che non può essere
minimizzato. Questo lavoro si propone di stimolare gli scienziati affinchè considerino e riflettano sui possibili impieghi
futuri dei
loro risultati (in termini di etica e rischi
per l'uomo e per l'ambiente). Esso con umiltà suggerisce loro di
coniugare la ricerca con un principio di "Ricerca Socialmente Responsabile", ad esempio affrontando l’argomento
dell'applicazione di nuovi nano-farmaci nella terapia del cancro (suggerisce anche i possibili limiti di percezione dei
problemi dei ricercatori e suggerisce poche modeste proposte di azione finalizzate al progresso sociale) .
71
Introduction
The recourse to the four principles of Beauchamp and Childress’ theory:
‐
Doing Good (Beneficence),
‐
Avoiding harm (Non-Maleficience),
‐
Respect of autonomy (Autonomy Protection), and
‐
Justice (Protection of Equity/Justice),
are a set of values commonly used today, in ethical analyses but only sometime by scientists involved in the “Kwaï river”
paradigm exploration and through mono-disciplinary research improvement of specific knowledge (1, 2). In this respect,
emerging applied research poses some specific health and ethical questions which have to be taken into account at the
beginning of an innovative research project or, if not, at least when the technologies are developed for new applications,
leading to possible crisis and rejections. It is indeed the success of the scientific method which has succeeded in leading
Society to the present high technological level. But, with crisis after crisis, it is now necessary to raise the question of
the place of the “arrogant intelligence” of Science and emerging heavy Technologies when, for example, reserves are
decreasing and when social order is being profoundly brought into question by its technological contributions leading to
pollution, improved control of citizen, des-humanization, etc. (3). As explained by Demortain (4), the “risk society” (in
the Beck sense (5)) is a controversy society and science has a lot to do with this, even if sociologists and
anthropologists of risks have shown that the classical ideal of objectivity is unattainable. In fact, as obviously proved by
crisis and loss of confidence on emerging technology, dissensus seems to be rule! The problem is that we do not know
how to imagine the future world without strong connection with the machines. Do the Humans again know how to
reproduce themselves without technical implements or devices? Our life already passes by a co-dependency with the
machinic system (6). In this respect, how to promote a social progress for the Society at whole? Finally, the aim of this
paper is to highlight new and present specific and cultural issues not currently in debate but which merit attention of
policy makers engaged in decision making on nanotechnologies for health.
The frame of action
At the beginning of 1970s, the preoccupation for opinion was that of an elite, a specialized body, not at all ready for
discussion with social representative and then to change its decisions. Besides, the context of the “30 glorious years” did
not encourage in the re-examination of practices up to the emergence of an almost revolutionary process, that of May,
1968 in France. The desecration of the powers, which was a visible consequence, was associated with emergence of new
spokesmen on the agenda. In effect, new interlocutors were introduced in the “decision-making game” in the name of
populations, of the environment, favor particularly to allow claims for the Society granted by mass media. This new
situation besides illustrated the political and business environments behaviors: arbitrary power, economic interest,
rationalization of the budgeting choices. Crisis appeared like that of asbestos disease, the “mad cow” disease, etc. (7).
Since few years, the research of a modus vivendi between stakeholders lead to decisions considered representative of
an “economically and socially optimum”. Nevertheless, the transition from a government by rational “elites” to a new
storytelling developed by some medias, acting with new opinion leaders/ideologists, involved in some “socially correct”
discourses, risks to shift decisions with no direct link with a real democracy…(8).
“Jean-Jacques Rousseau feared it at his time: the part covered by sciences and technologies in the modern societies has
fallen into decay the irenic understanding of democracy” (9). In the research life, this movement is in fact only very
recent because the link of new knowledge application is not visible, what still allows, by confinement, a functioning of
the academic world very slightly under social control. They remain under the deficit model of science. However, like
during the National debate on nanotechnologies, the pressure which is exerted on the decision-makers implicates new
responsibilities and new behaviors… (10). Then, ethics attains academic research system, even if it is in its door only…
One of the reasons of this slow emergence is linked to the necessity to negotiate with the society (time consuming)
while science works under time pressure in spite of certain opinions (11): Competition, efficiency, peer evaluation, etc.
The publications of the EU research programs are completely illuminating on this aspect which moves away the world of
the research of a real scientific democracy.
In 2002, in “Converging Technologies for Improving Human Performance” (12) (context NBIC for Nano, Bio, Info,
Cognition), NSF from the USA hired the debate on the optimization of the human capacities, producing an impact on the
elaboration of ethical norms, on what a human being should be (13).
72
Now, in a society where performance and
surpassing oneself are more and more accepted norms, the individual is more and more solicited to manufacture up to
the concrete modeling of the human body (14). In this frame, where the ethics has a distinguished place, aiming
objective the improvement of health, one of the contemporary concerns, benefits from a strong social acceptance (15).
Existent scientific and medical advances linked with nanotechnologies appear with, in communication, billing of a made
easier diagnosis, an ameliorated healing and, in a more hidden way, that to transform the body with a view to
augmenting its capacities (ideal of perfection) through re-engineering of the Human body. Obviously, technologies of
medical care which are under development can be of use for other lateralized applications to change our physiological
"equipment” that tested in a hard desired context that of heavy diseases could be exploited in nowadays not desirable
frames. As signaled by Kurzweil (16), “As technologies become established well, there will not be any more barriers in
their use as the expansion of human potential”…The medical religious inclination today is at the level of technological
performances or prowess. The society encouraged by mass media, filled with wonder and fascinated, thinks that this
“medical progress” is without any borders, especially with the communication centered on the possible surrealistic
development of nanotechnologies… While science is, in principle, humanistic progress, medicine is able to make
miracles; this message constitutes a “religious” inclination… Every novelty seems to erase the traces of previous, but,
however, the progress in medicine constructs, in fact, on a back - bottom haunted by the anxiety of death, which is to
be bet out of the way and is left without voice (17).
In this unstable and evolving context, it is possible that medicine ignores the unknown territories of its impossibility...
So, discourses on the general implementation of the screening and medical care of all which is possible, by imagery,
nanotechnologies or by genetics, appear a bit vain, because screening makes of the deflecting a subject become then
more responsible of its future, an active agent of public health but also a subject to whom they give control, while it is
very safe in situation of mastering (17).
The more basic vision of the authors is that several prioritized questions have to be solved before a pacific use of
devices by citizen: the first is the absence of any risks induced by passive exposure (during fabrication, use or
recycling), and the second, the question of ethics. Often, the problem of the production of miniaturized devices and
systems is generally hidden by the global use induced by the general integration during industrial production. As an
example who knows what contain a smart phone or a car? For a reductionist point of view, robots can be deeply
associated with ethical problems, computer and mobile phones, also, etc. But the authors have never seen a paper, in
which the HSE (Hygiene, Security, and Environment) quality of each elementary component is deeply questioned, when
ethics of new technology is promoted… This is a proof that several disjointed cultures are present and working in
specialized domains. The only case where ethics and HSE risks are sometimes associated concerns nanotechnologies.
For this reason, the notion of priority is more complex and, probably, the two domains have to be studied
simultaneously. But research is now associated with a neo-liberal understanding of state and economy. “The goal is a
slim, reduced, minimal state in which any public activity is decreased and, if at all, exercised according to business
principles of efficiency” (18).
Nanotechnology, a multidisciplinary scientific field undergoing explosive development, which refers to the design,
characterization, production and application of structures, devices and systems that have novel physical, chemical and
biological properties, by controlling shape and size at the nano-meter scale (1, 3), is subject to many controversial
debates, among scientists, but not only. The design and assembly of sub microscopic devices called nano-particles,
which are 1 to 100 nano-meter in diameter (19), are also the object of concern as to the safety of their use, and not
only in the general public (20, 21, 22, 23, 24, 25, 26, 27, 28). Potential toxic effects of certain nano-products have
legitimately conducted either the decision makers or the civil society to mobilise high level expert’s investigation not
only in France (24, 25, 26) but in most of the OECD member countries (27, 28, 29). Charters, codes of conduct,
guidelines and other such documents, are slowly adopted by institutions1 that promote Socially Responsible Research,
introduced with various status (contractual or not) in their rules and procedures (30).
At the early step of research for industrial applications, “basic science”, by the knowledge it acquires through research,
allows the ever faster development of oriented technical progress. To achieve this, researchers like those responsible for
1
The European Charter for Researchers, edited in 2005 by the European Commission, has been adopted by many French research institutions, the National Centre
for Scientific Research (CNRS) and the National Institute for Research in Agronomy (INRA) among others. Many other countries have also elaborated such
document, Australia (Australian Code for Responsible Conduct of Research) and the USA (NIH Policy on instruction in the responsible conduct of research),
among others.
73
work scheduling rely on bases de reductionism which for a long time has made science successful (mono-disciplinary
approach). Meanwhile, complexity and interdependence are likely to be at the origin of emerging risks not perceived by
society, and even less (?) by those at their origin. In order to modify the researcher’s efficiency culture a principle of
“Socially Responsible Research” (SRR) has been proposed (30) and applied at CNRS level in the INSIS Institute
concerned by engineering sciences. The SRR proposal corresponds to a new socially vision of the classical mode 2 of
research activities and will make all participants in a research program more reflexive (31). “In mode 1 problems are set
and solved in a context governed by the, largely academic, interest of a specific community. By contrast, Mode 2
knowledge is carried out in a context of application. Mode 1 is disciplinary while Mode 2 is trans-disciplinary. Mode 1 is
characterized by homogeneity, Mode 2 by heterogeneity. Mode 1 is hierarchical and tends to preserve its form, while
Mode 2 is more heterarchical and transient [...]. In comparison with Mode 1, Mode 2 is more socially accountable and
reflexive. It includes a wider, more temporary and heterogeneous set of practitioners, collaborating on a problem
defined in specific and localized context […]. In Mode 2, research groups are less firmly institutionalized; people come
together in temporary work teams and networks which dissolve when a problem is solved or redefined” (31, 32). In SRR
the researchers cannot lean any more on knowledge, exclusively acquired as pure scientists, because social knowledge
also plays an important role (32).
This is because the issue, is on which research is based, cannot be answered in scientific and technical terms alone. In
the mode 2 and in the SRR, the research towards the resolution of these types of problem has to incorporate options for
the implementation of the solutions and these are bound to take into consideration the values and preferences of
different individuals and groups that have been as traditionally outside of the scientific and technological system. The
difference between the two proposals is that, for SRR, all the ethical and risks activities have to start at research level in
order to develop a new culture of the research activities (opening and interdisciplinary considerations)… Taking into
account the present mentalities, the object of the present paper is to show that it is urgent for scientists to be more
concerned about the future of the artifacts they create or allow to be created. Finally, the central goal is to serve the
ends of society, helping to construct more effective policies for science, technology and innovation, which in turn will
yield greater benefits for Humans (33).
In this respect, Society is increasingly demanding accounts from those whose functions have led them to the current
situation, driven, without their ever having been questioned, and with considerable media and even advertising back-up,
by the obligation to form part of an inevitable progress. This situation is leading more and more frequently to active
groups obsessively raising the question of whether the technology has indeed been developed with Man in mind, to
serve something, or for less respectable objectives…
Towards Nanodrugs…
In either case, the development of nano-medicine, the application of nanotechnology for the diagnosis and treatment of
human disease, should be oriented through the lenses of the above mentioned driving forces, thus handled with special
care. Compared to research in techno-sciences, scientists who initiate research in the biomedical field have obviously
more integrated ethical issues in their processes (34). Among the explanations, we retain the consequences of some
major health crisis such as the use of thalidomide and the cancer of the uterus latter induced in the offspring,
worldwide, the scandal that followed the Tuskegee syphilis experiment in the USA, or the asbestos induced
mesothelioma in factory or construction industry workers, notably in France. Today, risk analysis seems inclusive of the
culture of most medical scientists (35).
At the same time, in this important health field, crises are occurring in developed countries induced by a partial
transparency in authorizations of new drugs applications in health services (36). The concerned Agencies are stressed by
reduced budgets, the pressure of the pharmaceutical industry, the need of medical innovation, etc. In practice, the
global cost for the safe development of new efficient drugs has “largely increase” (indirect effect of complexity mastering
in association with more and more complex authorization procedures), leading to effects on early stage of research [36].
In this situation, the effects of used drugs on the environment, the long term health effect on patients, on the health
services staff, etc. are not always studied…
The search of the better productivity efficiency of applied technological research leads to support highly qualified
research units (classically known by their disciplinary peer evaluation). In this respect, time, financial and cultural
constraints lead to a research output centered on the main domain of interest of the research action, detrimentally to
74
other aspects considered as secondary or to be by passed/studied by other researcher’s populations (possible
responsibility transfer to others; cf. supra). The absence of pressure from decision makers for a better integration of
knowledge for a socially responsible research including ethics can increase the gap between technology and an “active”
social acceptance of an innovation, even in some attractive situations, like nano-drugs (37).
In any cases, it is important to recall that responsibility must be a tool which prevents or avoid science to follow its
technological search, except in apparently unacceptable situations (which have to be specifically treated by ethical
committees). It is necessary to favor the multiplicity of points of view, in other words, to have a more voting approach
of science, more controversial, to play all in all new forms of voting rationalism because collective: learn to be able of
constructing with experts issued from different domains an object and a scientific problem. In this respect, the
organization of debates, led by research units can be a means to link up better sciences, technologies and Society.
U. Beck (5) points out that “it is no longer the extent of the risk which changes but its “scientification” which no longer
allows the discharge of its responsibilities onto Nature”. Researchers can no longer remain in their cozy silo, and should
take more of an interest in the World by returning, albeit modestly, to a less modular, less mono-disciplinary production.
They should participate in the co-ordination of productions with a view to achieving an operating efficiency of interest to
society (38), and then open out onto a new culture less formatted by the reductionism of linear thought (30). The SRR
approach is one means of closing the gap with a society that is worried, poorly trained, poorly informed, with changing
desires (39). It is at the outset of this gap - closing operation that it will perhaps be possible to avoid untimely and
random checks, but this imposes a responsible character ultimately new in its expression.
According to the large number of innovations present now in or close to the market, as proved by literature analysis, it
is not possible to cover and master all the range of the risks for the populations and the environment… Indeed, the
technological progress develops proposal without any robust risks assessment coverage. Nevertheless, for safety
problems, the SRR approach, connected with a positive attitude of exploration of the precautionary principle can be used
for the proposal of good protection against pollutants of citizen, workers or in general for maintaining the quality of the
environment. For more complex ethical situations, researchers have to enlarge their specific mono-disciplinary culture
and their vision in order to develop interdisciplinary link with other disciplines (i.e. social sciences) before to discuss with
society representatives or stakeholders… The goal of the presentation is then to express with one example, that it is
possible to reach a certain confidence between emerging innovations (nano-drugs, clean processes, nano-sensors,
“nanobots”, etc.) and the public needs, whishes or demands... if the global research system will support a large
interdisciplinary action.
Application to Nano-drugs
General considerations
The relationship between science and Society is likely to have a significant impact on the future of the research system.
This includes how science feeds back its knowledge from society: How the scientific organization adapts to the need for
public accountability and whether self-regulation is adequate to deal with some misconduct are open-ended questions?
How science will go about handling ethical issues and addressing controversial developments in area high public interest
will help determine the relationship between science and society? (40).
To hire the cogitation concerning the perception of the necessary openings between a divided up science and the needs
of the society in a humanist frame, the authors have explored two actions. Both operations concern the intellectual
world, of which that of researchers. They are therefore led under the patronage of categorization of membership and a
social rather modest distribution of knowledge. This biased aspect is necessary to take into account actual
visions/understanding of this world and to estimate the possibilities of commitment for a possible agreement between a
technological innovation, of which essential effects are the object of studies, and a confident social agreement more
inscribed in long term (41).
Pilot survey
The first preliminary study allows to understand differentiation better than the researchers make (principally the
engineering sciences) to say it and make it in the real world. It corresponds to results issued from e-mailed
questionnaires, summed up below (3).
The decision to conduct a qualitative survey rose from the need to dispose of first hand and shared information
regarding the level of knowledge of our specific study object, nano-medicine and more precisely PDT using nano-
75
particles, in the educated public [Photodynamic therapy (PDT) is an important emerging research field for the
development of nano-scale therapeutics (42, 43, 44). Photodynamic therapy involves the use of light, photo-sensitizers
(PS) and oxygen. The photo-sensitizers, after excitation with light of an appropriate wavelength, can transfer their
energy from their triplet excited state to neighboring oxygen molecules (45). Reactive Oxygen Species (ROS) and
singlet oxygen (1O2), which is commonly accepted to be the main cytotoxic species, are formed and lead to the
destruction of cancer cells by both apoptosis and necrosis. PDT efficiency depends on the photo-sensitizer’s ability to
produce ROS and 1O2, oxygen availability (46), light dose and photo-sensitizer concentration in the treated area]. It was
designed to be conducted by questionnaire, addressed electronically to a selected population ranging from researchers
specialized or not in the field of PDT to the educated social body to investigate their perception of the research
conducted in the field of nano-medicine in general, PDT in particular, and the associated potential health hazards abd
ethical considerations along with the means of protection.
The questionnaire was elaborated with the intention to investigate different knowledge regarding medical research. A
series of questions were organized in 3 sets that covered the following items:
-
General information on nano-medicine and the pre-requisite specific to the initiation of a clinical assay;
-
Choice given to answer either yes, no or don’t know to the same questions regarding the different phases in the
development of a new product in medical research;
-
Questions pertaining to the special field of clinical research.
The target population was selected to cover an audience educated enough to be aware of the specific research field
represented by nano-medicine (3).
Results of the pilot survey (3)
In fact, the questionnaire covers a wide sample of disciplinary and applied scientific fields. It was conceived to collect
information on the competencies of different actors or social groups on our specific field of study: photodynamic therapy
using nano-particles in cancer therapy. The previously described limitations and biases, notably in the recruitment of the
target population (screening and casting), make our pilot survey totally unsuited to be representative for expression of
an educated population’s opinion, but still useful for our initial and immediate purpose. Moreover, this could also be an
interesting preliminary and very instructive phase to determine feasibility of a similar survey on a larger scale.
In summary, our survey, providing note worthy elements of information that served our need to better situate the use
of nano-particles in PDT as a field of relevant clinical research.
1.
2.
Respondents are rather competent on the central theme.
Association between creativity and interdisciplinary approaches is subject to a real debate, partly due to lack in fruitful
interactions between the many scientific fields and insufficient funding.
3.
Precautionary approach indispensable to conducting clinical research seems completely unknown, and in particular the
health & safety issues. Ethics is absent at the research stage. The discourse refers only to the existence of regulation
without explicit mention of risk management in this context of uncertainties.
4.
As a whole, risks identified are centred on those incurred by patients who are concerned with the intake of nano-drugs
in clinical research. The same observation applies when it comes to the elimination of those substances which may
cause damage to the environment and workers.
5.
Medical doctor-patient relationship in their interactions is well described, as well as the role of the physicist in relation
to his patients.
Concerning specifically health and safety preventive measures, some comments made can be presented:
1.
The absence of a real culture of prevention or of ethics in university settings, probably related to the absence of
2.
The need, as a priority, to upgrade the health and safety equipment and installations in the universities..
support/control by the relevant authority, along with a pressure to deliver immediately.
3.
The question of the information of the personnel, and more broadly of the citizens vis-à-vis the traditional dialectic of a
priori criticism of the precautionary principle is raised. Moreover, it can sustain the public’s demand of an As Low As
Reasonably Achievable (ALARA) type of leadership (35).
4.
The notion of independence of the experts in general and the scientists in particular when conducting safety studies and
ethical expertise.
76
Local expertise at lab scale
The second study corresponds to a local study, led inside the Laboratory LRGP on the case of PDT (system using nanodrugs for the treatment of certain cancers), allowing to analyze aspects of understanding of ethical questions by the
concerned researchers, ways of cultural progress and a certain return of experience.
From the best possible knowledge on the diversity of presentations, there is possibility of disposing specific interests of
the different actors of a clarification of their role, promoting diversity and possibility of deepening expertise on particular
axes, but also of searching other partners allowing, as much as possible, to a real balanced debate. In this distribution
on important of unknown, it must be possible to define the state of the uncertainties of scientific and technical
knowledge, of approximations of knowledge, abuses of interpretation, limits of competence, to measure, at least the
importance of open questions and interrogation marks. In innovative experimental research, the knowledge of risks
linked to subjects, materials, chemicals, artifacts, is only rarely stabilized. This context implicates therefore a reinforced
protection of the working environment of the researcher or, more broadly of the environment, to avoid unacceptable
risks for the Society, risks which are in a context where does not exist regulation issued from the mastering of risks
paradigm.
Decisions linked with the use of the precautionary principle can be translated by:
- A temporary ban (or final): request of moratorium (example: carbon nano-tubes);
- A restriction of usage;
- An “adapted” information toward specialized social bodies;
- Specific researches of deepening on risks / hazards for the researchers and the general population;
- A "simple" alert;
- An irresponsible standby.
In situation of uncertainty, several criteria should be estimated on impact of envisaged research program: acceptability,
observability, reducibility on one hand, irreversibility, severity, plausibility on the other hand. These elements leaning as
much as possible on all validated knowledge must show the "consistency" of risk (potentially supported, credible,
hypothetical potential, etc.). On these foundations, Chevassus-au-Louis (48) offers to use a hexagonal mapping such as
those introduced on figures 1 and 1bis. This one was accomplished by consultation of researchers and professionals of
different origins: hygienists, specialists in public health, physicists, physicians, chemists, jurists, ethics experts.
Indeed, the consultation of different partners expresses itself across a revealing diversity of visions and cultures of the
dimension, complexity and the tensions of emergent fields. It results from its difficulties of "cooperation" between hard
heterogeneous cultures. In fact, multiple driving forces between disciplinary technological, scientific purposes, progress
vision, transfer of knowledge to the Society, environmental and public health, ethics, etc. already exist for the scientists.
These separated characteristics often lean on an appearance of shared definition. Indeed, the new domain defines itself
probably at least by purposes, of "systems of sense” as much as by a field of question settings or effective problems or
a list of industrial results, etc. The existence of a certain fuzziness perhaps owed to an absence of individual clarification,
but also to the possibility of exploiting this frame not stabilized to act in a hired way. In that case, they can wait for
dysfunctions, or even for breaks of dialogue between partners. Of this fact determined in cases where the uncertain
reigns (nuclear waste, nanotechnologies for instance), the knowledge of the diversity of representations is a necessary
precondition for a positive and honest exchange leading to a “satisfactory” assessment.
Several considerations / centers of interests can be explored:
1-
Disciplinary considerations: new knowledge, innovation, creation of wealth, technical progress, care and medicine,
2-
Ethical and moral considerations: prevention, ethics of the Human being, preservation of life, solidarity between
3-
Daily environment: nuisances, pollution, hygiene, security, health, stresses, living conditions, comfort,
4-
Political and social frame: creation of new jobs, social control of decisions, civism, democracy, local solidarity
technical well-being, risks, toxicity, resource management,
young and older generations, sustainable development, long term effects,
(example of the waste management), citizen omnipresent control and linked security, terrorism.
77
Figure 1 - Collective analysis of exploration of the Precautionary Principle taking into consideration : 1- Social
Acceptance (medical case); 2- Observability; 3- Plausibility; 4- Severity; 5- Irreversibility; 6- Reducibility – In the nanodrugs for PDT case, survey of literature and classical prevention seems sufficient for research exploration of the topic…
Mapping related to "action" indicators
1
1
0,8
0,6
6
2
0,4
SURVE
Y 0,2
0
5
Série1
Série2
3
4
Figure 1-bis - Case of free carbon nano-tubes leading to the demand of the use of ALARA methods and a massive
reduction of exposure…
1
1
0,9
0,8
0,7
0,6
6
2
0,5
0,4
SURVE
Y 0,3
0,2
0,1
0
5
Série1
Série2
3
4
On the basis of the results (to be periodically revisited because they are function of the advances of knowledge), it was
decided to follow research on nano-drugs, because representing decisive advantages in relation to possible progress for
the society. Let us point out however that this position concerns only the research context which cannot be independent
himself from relations with the professionals and the society for a potential success in terms of transfer science-society.
This fragmentary analysis is therefore only a support to decision. In any case, the study of problems in this initial stage
is probably fastidious and only rarely financially supported. Anyway, taking into account of peculiar elements as those
introduced here in a global process the approach can have a low success induced by a system working in disciplinary
silos and by association of organizations having disjunctive interests.
So, in the case of nano-drugs of PDT type, it is clear that concerns turn to aspects of feasibility, expense and especially
therapeutic success, just like what was played for the chemotherapy. The ethical aspects and of risks for health were put
in the second horizon plan because the short term rehabilitation of patient’s health is considered as priority. And,
according to INRS (49), medical staff displayed in spite of them in products of chemotherapy begin complaining about
diseases (cardiovascular and cancers) moreover, the ethical aspects are under the responsibility of the doctors
intervening in group of decision. Mass is not therefore said!
78
In debates inside the lab, science in the field of nano-medicine appears to answer a principle of construction of
integrated devices to accomplish experimental implements which are going to produce material effects. There is
therefore intentions and research of a real innovative performance. In this frame, activity financed on contracts is
translated by belief that utilitarian regime serves external social interests in those of the scientific community, that is to
say in scientific deepening and in the application of concepts, led by other actors. It is not then easy to sketch the
responsibilities of the researchers because numerous dependencies which lead our relationships with technical
innovations is only very seldom envisaged inside a research units involved in “hard sciences". And apparently, in the
concerned domains, creation of systems introduces a vital solidarity with the Man …
A return to socially responsible research
The absence of reliable information in terms of possible risks must be translated by the use of the precautionary
principle, as currently laid down in the law. This context therefore leads to being committed to the definition of the
conditions
of
maximum
protection,
not
only
of
research
operators
but
also
of
those
around
them
(environmental problems). Of course, the strict application of this principle has no link with any ethical consideration.
If this information can be communicated easily, the situation should then be examined case by case to define the
research conditions at “minimum” risk on a local scale and, at the same time, interdisciplinary discussions will be helpful
for examination of ethical problems. As per the example of the CSR (Corporate Social Responsibility) (50), or the SD
(Sustainable Development) Frame, it may be useful to propose a “socially responsible research” (SRR) “label” which is
granted to laboratories:
- Respecting the «ALARA» (as low as reasonably achievable) principles or general precautions;
- Committing themselves to an analysis of the knowledge of the risks and ethical problems in order to (re)define the
appropriate protection and information modes, which are the subject of a written charter of operation of a “labeled”
research team and communicable to the tutelage? This approach makes the teams more responsible and avoids entering
into an “offense of ignorance”;
- Informing the stakeholders, decision makers, or more generally the Social body.
This label must probably be issued by an organization independent of the tutelage of the researchers which would be at
the origin of a specific charter applicable to new technologies that are associated with insufficient scientific knowledge of
the hazards and then to risk management for a part, ethical problems for the other. The case of nanotechnologies/nanodrugs serves as the demonstrator of this new type of functioning of science.
Based on the principles of the CSR (38), the foundations of the SRR, elements of sustainable development charters,
could be the following (30):
- The SRR covers in the activity of a research team the social and environmental matters;
- The SRR is not and should not be separated from the action strategy of the research laboratory as it is about
integrating social and environmental concerns into the activities;
- The SRR is a voluntary concept;
- An important aspect of the SRR is the way laboratories interact with those directly committed, both internally and
externally (employees, clients, close environment, tutelage, partners, etc.).
To do this, the implementation of the SRR implies an enhanced and updated perception of the environment as well as
respect for the balance of the interests of the parties committed. In this sense, the compulsory opening towards what is
not directly productive perturbs, breaks the research dynamic of a team (like the quality management in research, etc.).
In this framework, to change the culture of the researchers, it will surely be necessary for the tutelage to contribute
signals of a strong willingness to support: recognition of the SRR label, training, modification (partial?) of the evaluation
modes of researchers and research units, support to an international labelling scheme, etc. But, this wish is only under
progress for the moment...
Provisional conclusion
Beck (5) points out that “it is no longer the extent of the risk which changes but its “scientification” which no longer
allows the discharge of its responsibilities onto Nature”. Researchers can no longer remain in their cozy silo, and must
take more of an interest in the World by returning, albeit modestly, to a less modular, less mono-disciplinary production
79
taking into consideration risks for today and tomorrow. They must participate in the co-ordination of productions with a
view to achieving an operating efficiency of global interest to society (37), and then open out onto a new culture less
formatted by the reductionism of linear thought (39). The SRR concept is one means of closing the gap with a society
that is worried, poorly trained, poorly informed, with changing desires. It is at the outset of this gap-closing operation
that it will perhaps be possible to avoid untimely and random checks, but this imposes a responsible character ultimately
new in its expression. In the case of nano-drugs, we show that it is possible to enlarge the innovative vision to a more
broad thinking, able to decrease the gap between technical novelty and Society.
With LOLF (French law of Finances) and AERES (National Scientific Evaluation System), the panorama changes: other
logic, other methods. The National research system is put in front of new processes of control and of new responsibilities
centered more and more on results rather than on means to acquire them. This new manner of governing is meant to be
parried with the finery of neutrality and objectivity, it has a name: governance. This one asks for means of so possible
checking in anticipation to restrict the catches of risk. Art to quantify and to define robust indicators been part of modes
of governance because it consists in transforming crabbed and complex data into easily readable and “eloquent” figures.
The self-government, factor of future of research (?), however does not allow a control, or an easy management,
because it is not possible to master creation in an unequivocal way, for several reasons:
- The growing complexity of specific knowledge detained by the researchers;
- Complexity and ambiguity of the scientific problems which they confront;
- The material and organizational conditions of their action, at least in the stages of kickoff of a new research.
It follows from this situation a certain use by certain researchers of the interpretability (or even of the misappropriation)
of what is not determinist and unequivocal. It means that if management is confronted to the existence of cognitive
interpretations, it defines itself by a “blurred order of the local interpretations of the actors of research” (50).
Whatever the case, this radical change assumes a genuine societal willingness if we wish to make research a socially
useful and enduring tool in a world which itself is exploring new paradigms. However, as A. Einstein wrote, "No problem
can be resolved without changing the mind of he/she who brought it about" (51).There is however a strong risk of this
agreement being a rhetorical device taking the lazy and easy way with slogan-based imprecations which are essentially
reduced to a display. It has been said, so it is as if it has been done! If convincing were needed, it might be the display
of a somewhat unfounded willingness to reduce the production of carbon gas for the environment. In the absence of
goodwill, which is without doubt probable, it will unfortunately still be possible to carry out disciplinary work that is
fortunately useful (with some limits).
Does the causal and enlightening case of new technologies, supported by all the decision-makers, not risk at the end of
the day obscuring this necessary reappraisal of the role of research on risks in a world that is increasingly eluding the
desires of humans? The international context of nano-medicine still provided ample room for discussing, studying and
elaborating the social meaning of the topic, which enabled the interested scientists to be more prepared for the right
moments to bring in the notion of socially attractive nano-drugs development for optimized and efficient cancer
treatments (52, 53)... So that mentalities change, or give the appearance of change, it is necessary that the collective
vision acquiesces in the disappearing of ancient and sticks to the inevitability of the new, it is necessary that a general
agreement appears to justify the modification of progress without disrupting it absolutely, it is necessary to guarantee at
the same time change and continuity… (54). But, to identify problems in their precocious stage and in acknowledge
potential hazard demand a wise judiciousness and preshow feelings. Apathy is not any more allowed to us. Any
negligence makes us guilty (55).
“Our culture dictates that we win: on the battlefield as well as in frantic economic or scientific competition… today
reaching the extreme limits of performance, martial violence and the economy; are we now so sure that we must always
win, and this includes the domains of the spirit?” (56).
80
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Corresponding Author: Jean Claude Andrè
Autore di riferimento: Jean Claude Andrè
83
La riforma della responsabilità medica in Italia
e la depenalizzazione della colpa lieve: criticità
LA RIFORMA DELLA RESPONSABILITÀ MEDICA IN ITALIA
E LA DEPENALIZZAZIONE DELLA COLPA LIEVE: CRITICITÀ
THE LEGISLATIVE REFORM OF MEDICAL LIABILITY IN ITALY AND THE
DECRIMINALISATION OF ORDINARY NEGLIGENCE: CONTROVERSIAL ISSUES
Montanari Vergallo G1, Frati P1, Zaami S1, Ciancolini G1, Correnti FR1, di Luca NM1
1
Dipartimento di Scienze Anatomiche, Istologiche, Medico Legali e dell’Apparato Locomotore,
1
Department of Anatomical, Histological, Medico-Legal and of Locomotive Apparatus Sciences,
“Sapienza” University of Rome, Italy
Citation: Montanari Vergallo G, Frati P, Zaami S, et al. La riforma della responsabilità medica in Italia
e la depenalizzazione della colpa lieve: criticità. Prevent Res 2013; 3 (2): 84-91. Available
from: http://www.preventionandresearch.com/
Parole chiave: riforma legislativa, depenalizzazione della colpa lieve, linee guida, responsabilità penale,
responsabilità civile, risarcimento dei danni
Key words: legislative reform, decriminalisation of ordinary negligence, guidelines, penal liability,
civil liability, compensation of damages
Abstract
Introduzione: Negli ultimi anni la Suprema Corte italiana ha affermato principi che hanno portato: a) ad un
aumento dei risarcimenti concessi ai pazienti e dei premi pretesi dalle assicurazioni, con conseguente aumento della
spesa sanitaria; b) alla nascita e alla crescita della c.d. medicina difensiva con importanti ricadute economiche.
Il legislatore ha cercato di porre rimedio al dilagare della medicina difensiva con la legge n. 189/2012.
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Obiettivi: Gli Autori illustrano le effettive innovazioni apportate dal legislatore al sistema di responsabilità medica
elaborato dalla giurisprudenza negli ultimi quindici anni.
Gli Autori analizzano la questione dell’idoneità della riforma a: a) eliminare le pratiche di medicina difensiva; b)
ridurre l’ammontare della spesa per risarcimenti; c) aumentare la serenità dei medici nell’esercizio della professione.
Metodi: Gli Autori analizzano gli effetti della nuova disciplina e li confrontano con i principi sanciti dalla Suprema
Corte in materia di colpa, responsabilità contrattuale e danni alla persona.
Risultati/Discussione e Conclusioni: La legge n. 189/2012 conferma che le linee guida non sono vincolanti.
Infatti, il medico che rispetta la linea guida può ugualmente essere dichiarato responsabile quando le circostanze del
caso rendevano non applicabile la linea guida stessa.
Tuttavia, la riforma afferma che, se il medico osserva linee guida che non dovevano essere applicate, la
responsabilità penale può essere dichiarata solo quando la sua condotta costituisce colpa grave. Dunque, il legislatore
ha depenalizzato la colpa lieve.
Questa nuova regola solleva innanzitutto problemi di incostituzionalità.
Inoltre, l’applicazione di una linea guida finalizzata anche a ridurre la spesa sanitaria potrebbe essere valutata come
colpa grave perché la Suprema Corte italiana afferma che la prevalenza dell’interesse del paziente sulle esigenze
economiche è una regola basilare.
Di conseguenza, il medico verrebbe comunque dichiarato penalmente responsabile.
Per quanto riguarda la responsabilità civile, la riforma afferma che, quando la colpa è lieve, si applica l’obbligo
previsto dall’art. 2043 del codice civile.
Sebbene l’art. 2043 codice civile riguardi soltanto il danno patrimoniale e la responsabilità extra-contrattuale, la
riforma non sembra poter modificare la natura contrattuale della responsabilità medica e l’obbligo di risarcire anche il
danno biologico e il danno morale.
Infatti, la legge n. 189/2012 richiama soltanto l’obbligo previsto dall’art. 2043 codice civile, ossia l’obbligo di risarcire
il danno ingiusto e non anche il tipo di responsabilità, se contrattuale o extra-contrattuale.
Inoltre, nella nozione di danno ingiusto possono rientrare anche il danno biologico e il danno morale. Altrimenti, la
riforma sarebbe incostituzionale.
Riguardo alla quantificazione del risarcimento, la riforma afferma che il giudice deve tenere conto del fatto che il
medico ha rispettato le linee guida.
Ma tale regola determina disparità di trattamento tra pazienti, perché uno stesso danno cagionato con lo stesso grado
di colpa lieve verrebbe risarcito con somme differenti a seconda che il medico abbia seguito o meno le linee guida.
Pertanto, la capacità della riforma di ridurre la spesa sanitaria per risarcimenti e per medicina difensiva appare molto
discutibile.
Abstract
Background: In recent years, the Italian Supreme Court stated principles that led to: a) an increase in damages
awarded to patients and premiums demanded by insurance, resulting in increased health care costs, b) the birth and
growth of the so-called defensive medicine with major economic repercussions.
The Italian legislator has tried to remedy the spread of defensive medicine by Law no. 189/2012.
Objectives: The authors illustrate the actual innovations made by the legislature in medical liability system
developed by the Italian Supreme Court in the last fifteen years.
The authors analyze the question of the suitability of the reform: a) to eliminate the practice of defensive medicine;
b) to reduce the amount of expenditure for compensation; c) to increase the serenity of the doctors in the practice.
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Methods: The authors analyze the effects of the new rules and compare them with the principles laid down by the
Supreme Court on negligence, contractual liability and personal injury.
Results/Discussion and Conclusions: Law no. 189/2012 confirms that the guidelines are not binding. In fact, the
doctor who meets the guideline can also be declared liable when the circumstances of the case made not applicable
to the guideline itself.
However, the legislative reform states that if the physician observes guidelines should not be applied, the penal
responsibility can be established only when the conduct constitutes gross negligence of the doctor. Therefore, the
legislator has decriminalised negligence.
This new rule raises first issues of unconstitutionality.
Furthermore, the application of a guideline also aimed to reduce health care spending could be considered as gross
negligence because the Italian Supreme Court has stated that the predominance of the patient's health over
economic interests of medical facilities is a basic rule.
As a result, the doctor would still be convicted.
With regard to civil liability, the legislative reform states that when there is ordinary negligence, the duty laid down in
article 2043 of the Civil Code applies.
Although the article 2043 of the Civil Code relates only to the pecuniary loss and non-contractual liability, the reform
does not appear to change either the contractual nature of the medical liability or the obligation to compensate also
the biological damage and the loss for pain and suffering.
In fact, the law n. 189/2012 refers only to the obligation under article 2043 Civil Code, i.e. the obligation to
compensate contra ius damages. As a result, article 2043 does not refer to the nature of liability, whether contractual
or non-contractual.
In addition, the concept of contra ius damage may also include the biological damage and the loss for pain and
suffering. Otherwise, the legislative reform would be unconstitutional.
Concerning the quantification of damages, the reform states that the court must take into account the fact that the
physician has complied with the guidelines.
But this rule determines unequal treatment of patients because the same damage caused with the same degree of
negligence would be compensated with different amounts depending on whether or not the doctor has followed the
guidelines.
Therefore, the suitability of the reform to reduce health costs for compensation and for defensive medicine is very
questionable.
Introduzione
L’evoluzione giurisprudenziale in materia di responsabilità medica è passata da un orientamento tendente a valutare
l’operato dei medici con comprensione e benevolenza all’attuale sistema caratterizzato da: a) rilevanza della colpa
grave soltanto in casi eccezionali ed esclusivamente in ambito civilistico; b) inversione dell’onere probatorio in ambito
civilistico; c) tendenza ad accertare la colpa sulla base della sola violazione oggettiva di un obbligo di diligenza,
prudenza o perizia (standard of care) senza indagare sempre, e con il dovuto approfondimento, l’effettiva possibilità,
per quel singolo medico nel caso concreto, di tenere la condotta corretta.
Tale evoluzione ha portato: a) ad un aumento dei risarcimenti concessi ai pazienti e dei premi pretesi dalle
assicurazioni, con conseguente aumento della spesa sanitaria; b) alla nascita e alla crescita della c.d. medicina
difensiva con importanti ricadute economiche. I dati italiani più significativi relativi alla diffusione della medicina
difensiva sono documentati purtroppo da rapporti settoriali e non su grande scala nazionale. Fra i principali possiamo
ricordare: 1) il rapporto annuale del Tribunale per i Diritti del Malato (dal 1999); 2) le rilevazioni dell’Ania (The
National Association of Insurance Agencies), nel documento, presentato a cadenza annuale, “L’assicurazione in
Italia”; 3) un’indagine capillare condotta dall’Ordine dei Medici di Roma nel 2008.
Il legislatore ha cercato di porre rimedio al dilagare della medicina difensiva con il c.d. decreto Balduzzi, che, proprio
in materia di responsabilità medica, è stato radicalmente potenziato in fase di conversione nella legge al fine di a)
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ridurre la pressione gravante sui medici per il continuo rischio, e talora minaccia, di azioni giudiziarie; b) arginare
l’elevato livello di spesa sanitaria dovuta alle pratiche di medicina difensiva e al costo dei risarcimenti liquidati ai
pazienti dalle sentenze.
Obiettivi
Un primo obiettivo del presente contributo consiste nell’illustrare le effettive innovazioni apportate dal legislatore al
sistema di responsabilità medica elaborato dalla giurisprudenza negli ultimi quindici anni.
Conseguentemente, appare necessario domandarsi se le neovigenti regole realizzino gli obiettivi che il legislatore si
era posto, ossia: a) risolvano il problema della medicina difensiva; b) riducano l’ammontare della spesa per
risarcimenti; c) aumentino la serenità dei medici nell’esercizio della professione.
Metodi
Il primo passo consiste nell’interpretare la legge in esame secondo il significato letterale delle parole che la
compongono e coerentemente con le altre norme in materia. A tal fine, non si può prescindere dal dibattito
parlamentare che ha portato all’approvazione di tali previsioni normative.
Successivamente, il quadro normativo così delineato deve essere confrontato con i principi sanciti dalla Suprema
Corte in materia di colpa, responsabilità medica ex contractu e danni alla persona.
Risultati e Discussione
L’art. 3 del decreto legge Balduzzi n. 158/2012 disponeva che “Fermo restando il disposto dell'articolo 2236 del
codice civile, nell'accertamento della colpa lieve nell'attività dell'esercente le professioni sanitarie il giudice, ai sensi
dell'articolo 1176 del codice civile, tiene conto in particolare dell'osservanza, nel caso concreto, delle linee guida e
delle buone pratiche accreditate dalla comunità scientifica nazionale e internazionale”.
Tale disposizione non innovava particolarmente la materia ed, anzi, è stata autorevolmente ritenuta “inutile” (1).
Infatti, il potersi limitare a tenere conto dell’osservanza delle linee guida lasciava pressoché immutata quella
discrezionalità del giudice che, in particolare negli ultimi quindici anni, ha portato a un notevole aumento delle
possibilità dei pazienti di ottenere risarcimenti da parte di medici, strutture sanitarie e relative assicurazioni.
Dunque, la legge 8 novembre 2012, n. 189, di conversione del decreto Balduzzi, ha radicalmente modificato l’art. 3,
portandolo alla vigente formulazione, che recita: “L’esercente la professione sanitaria che nello svolgimento della
propria attività si attiene a linee guida e buone pratiche accreditate dalla comunità scientifica non risponde
penalmente per colpa lieve. In tali casi resta comunque fermo l’obbligo di cui all’art. 2043 del codice civile. Il giudice,
anche nella determinazione del risarcimento del danno, tiene debitamente conto della condotta di cui al primo
periodo”.
Da tale disposizione sembrano emergere quattro contenuti specifici: a) la rilevanza delle linee guida è meramente
orientativa, in quanto implicitamente, ma chiaramente, si afferma che la scelta di attenersi alle stesse può costituire
colpa; b) nei casi in cui il medico segue le linee guida, la responsabilità penale è limitata alla sola colpa grave, mentre
è esclusa per colpa lieve; c) anche in mancanza di responsabilità penale, il medico è tenuto a risarcire il danno
ingiusto ex art. 2043 c.c.(responsabilità extracontrattuale); d) l’aver seguito le linee guida (per errore determinato da
colpa lieve) deve essere tenuto in considerazione dal giudice al momento di quantificare il risarcimento e, quindi,
dovrebbe portare ad una riduzione dell’importo liquidato in favore del paziente.
Soltanto la prima di queste affermazioni risponde ad un insegnamento consolidato, mentre le altre sono piuttosto
controverse e la loro effettiva portata innovatrice può essere agevolmente vanificata.
Passiamo ad analizzarle, seppur brevemente.
Riguardo alla rilevanza delle linee guida, non è affatto contraddittorio ipotizzare la colpa nonostante il rispetto delle
linee guida (2, 3).
Infatti, anche quando elaborate da autorità pubbliche come il Ministero della Salute o una Regione, le linee guida
conservano comunque carattere orientativo e mai tassativo perché, proprio nell’ambito medico di cui le linee guida
fanno parte, l’esigenza di personalizzare le scelte diagnostiche e terapeutiche rappresenta un imprescindibile principio
“rigorosamente scientifico” (4).
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Inoltre, tale rilevanza orientativa delle linee guida è, per giunta, temporanea in quanto il progresso della medicina
comporta il loro necessario aggiornamento (5).
Anche la Suprema Corte ha condiviso tale impostazione affermando che l’adesione alle linee guida non consente di
escludere la responsabilità penale del medico, se il paziente presenta un quadro clinico che impone una condotta
diversa da quella contenuta nelle linee guida” (6).
Sebbene il legislatore non lo affermi espressamente, dalla rilevanza orientativa delle linee guida dovrebbe, per
coerenza, discendere che anche l’inosservanza delle stesse non dimostra di per sé la colpa del medico.
Dunque, sotto questo profilo, il legislatore sembra essersi mosso correttamente e coerentemente con le peculiarità
della medicina.
Per quanto riguarda la limitazione della responsabilità penale alla sola colpa grave, la riforma esclude la
responsabilità penale nei casi in cui, con colpa lieve, il medico applica linee guida che, invece, per le peculiarità del
singolo caso clinico, sarebbe stato meglio non seguire.
Dunque, come rilevato dai primi commentatori della riforma, il principio giurisprudenziale sopra riportato necessita
soltanto di una, ma determinante, integrazione: “Le linee guida non possono essere invocate per escludere la
responsabilità penale del medico, se il paziente presenta un quadro clinico che, macroscopicamente, impone una
condotta diversa da quella raccomandata dalle linee guida” (7). Ossia, la necessità di discostarsi dalle linee guida
deve essere “immediatamente riconoscibile da qualunque altro sanitario al posto dell'imputato” (8).
Tale disposizione pone almeno tre problemi: a) escludere la responsabilità penale per lesione colposa o omicidio
colposo in ragione della lievità della colpa riduce notevolmente la tutela, anche preventiva, del diritto alla salute, il cui
rango costituzionale, invece, dovrebbe comportarne la massima protezione; b) la gravità della colpa è concepita
dall’art. 133 c.p. come criterio di quantificazione della pena e mai come presupposto della responsabilità; c) la
prospettiva di ottenere una limitazione di responsabilità in caso di errore induce il medico a seguire sempre le linee
guida, finendo col condizionarne l’autonomia professionale, anch’essa valore di rilievo costituzionale (9, 10).
Nessuno di questi aspetti è stato preso in considerazione nei lavori preparatori.
Inoltre, anche a prescindere da tali considerazioni, e nonostante la prima sentenza che applica la riforma parli di
“depenalizzazione della colpa lieve” (11) proprio come il relatore della legge stessa in Commissione (12), sembra
presentarsi un problema intrinseco allo stesso art. 3 della legge Balduzzi.
In effetti, la riforma si riferisce alle linee guida accreditate dalla comunità scientifica, ma non ne offre esplicitamente
la definizione. Al riguardo, nessuno spunto per una ricostruzione deduttiva può essere ricavato dai lavori preparatori.
Invece, la giurisprudenza antecedente alla legge n. 8 novembre 2012, n. 189, ha prospettato l’esistenza di linee
guida funzionali alla protezione della salute del paziente accanto ad altre che, invece, sono piuttosto dettate da
logiche economicistiche incompatibili con il miglior interesse del malato. Di conseguenza, le linee guida
economicistiche non possono essere seguite perché deve essere data prevalenza al diritto alla salute del singolo
paziente (6).
Peraltro, anche successivamente all’approvazione della riforma, non sono mancati espliciti richiami alla perdurante
correttezza di tale impostazione (13).
Dunque, appare probabile che l’adesione a una regola di comportamento che, pur contenuta in linee guida, sia
ispirata non solo all’interesse del paziente, ma anche indubbiamente al contenimento dei costi, sia considerata dalla
giurisprudenza come una colpa grave sostenendo che la prevalenza del diritto alla salute del malato sulle “logiche
economicistiche” dovrebbe rappresentare una regola basilare per qualunque medico. Conseguentemente, la sua
violazione potrebbe integrare una colpa grave.
Tale conclusione, tuttavia, presenta due problemi: a) distorce il concetto di linea guida, perché non esistono linee
guida prettamente economicistiche ed altre esclusivamente finalizzate alla salute del paziente: ogni linea guida è
diretta ad indicare un corretto e proporzionato uso delle limitate risorse disponibili in funzione della protezione del
paziente (14); b) rischia di condurre alla sostanziale disapplicazione della riforma, che invece è coerente sia con
l’impostazione, sancita dalla Corte costituzionale, secondo cui il diritto alla salute deve essere tutelato
compatibilmente con le risorse disponibili (15, 16).
Quanto all’obbligo di risarcire il danno ex art. 2043 c.c., tale previsione induce a domandarsi se il legislatore abbia
portato l’intera responsabilità medica nell’ambito della responsabilità extracontrattuale.
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Per rispondere affermativamente a tale domanda non ci si può limitare a rilevare che la giurisprudenza è stata a
lungo orientata nel senso della natura extracontrattuale della responsabilità medica (17).
Infatti, questa tesi giurisprudenziale riguardava soltanto i medici dipendenti di struttura sanitaria, i quali, in quanto
tali, non hanno la facoltà di scegliere quando e chi curare. Mentre, nell’ambito dell’attività professionale privata, la
responsabilità medica è necessariamente contrattuale, presupponendo il classico e tipico scambio di proposta e
accettazione.
Inoltre, com’è noto, da molti anni la Suprema Corte ha consolidato il proprio orientamento nel senso di ritenere
sempre contrattuale la responsabilità del medico (18, 19).
Nei lavori preparatori, quest’aspetto non è stato affatto considerato. Quindi, non appare corretto sostenere che
l’intenzione del legislatore sia di applicare la responsabilità extra-contrattuale a tutta la responsabilità medica.
Anche la formulazione letterale della legge non obbliga a tale conclusione. Infatti, l’art. 3 si limita ad affermare che,
in caso di colpa lieve, “resta comunque fermo l’obbligo di cui all’art. 2043 del codice civile”, ossia l’obbligo di risarcire
il danno ingiusto.
Dunque, tale disposizione può ben essere intesa come riferita solo al diritto al risarcimento e non anche alla natura
della responsabilità.
Conseguentemente, la riforma non sembra porsi in contrasto con la giurisprudenza favorevole alla natura
contrattuale della responsabilità medica.
Anche sotto un altro e autonomo aspetto, tuttavia, la norma in esame appare poco chiara.
Infatti, com’è noto, la giurisprudenza ha, da tempo, sancito che l’art. 2043 c.c. riguarda soltanto il danno
patrimoniale, mentre al danno non patrimoniale si applica l’art. 2059 c.c. (20).
Di conseguenza, poiché l’art. 3 in esame richiama soltanto l’art. 2043 c.c. e non anche l’art. 2059 c.c., si crea il
dubbio circa la risarcibilità dei danni non patrimoniali, tra cui, per la richiamata e ormai costante giurisprudenza, il
danno biologico e quello morale (21).
L’esito applicativo di tale interpretazione dell’art. 3 consisterebbe, quindi, nell’impossibilità di risarcire i pazienti per
danni biologici e morali, almeno nei casi in cui ci si discosta da una linea guida con colpa lieve.
Tuttavia, tale interpretazione renderebbe palesemente incostituzionale l’articolo in esame per violazione sia del diritto
alla salute e del diritto all’integrità morale, perché entrambi rivestono pacifica rilevanza costituzionale ex artt. 32 e 2
Cost. (22), sia del principio di uguaglianza perché si risarcirebbero in modo completamente diverso danni
oggettivamente uguali per il sol fatto di essere stati cagionati in un caso con colpa lieve e in un altro con colpa grave.
Dunque, anche in considerazione del fatto che il legislatore non è vincolato al rispetto degli orientamenti
giurisprudenziali, appare possibile e necessario interpretare l’art. 3 nel senso di includere nel danno ingiusto,
risarcibile ex art. 2043 c.c., tutte le lesioni di diritti e, quindi, anche quella del diritto alla salute, cui consegue il
risarcimento sia del danno biologico sia del corrispondente danno morale (23, 24).
Pertanto, anche sotto questo profilo, la riforma appare meno innovativa di quanto sembrerebbe a prima lettura.
Riguardo, infine, alla regola secondo cui l’aver seguito le linee guida (con colpa lieve) deve essere tenuto in
considerazione dal giudice ai fini della quantificazione del risarcimento, si pone il problema del rapporto con il
tradizionale insegnamento secondo cui solo il risarcimento del danno morale da reato può variare in relazione, tra
l’altro, alla condotta del colpevole. Mentre, per quanto riguarda le altre tipologie di danno, il risarcimento deve essere
proporzionato alla gravità oggettiva del danno, indipendentemente dalla natura dolosa o colposa della condotta.
La riforma non sembra poter modificare tale consolidata struttura della responsabilità civile in Italia.
Infatti,
anche
la
sola
riduzione
del
risarcimento
dovuta
all’adesione
alle
linee
guida
determinerebbe
un’incostituzionale disparità di trattamento rispetto ai pazienti che subiscono il medesimo danno biologico (o
patrimoniale, essendo anch’esso oggettivo) a causa di una condotta medica non conforme alle linee guida.
Tale problema non appare risolvibile sostenendo che la norma si riferisce al solo danno morale.
In effetti, sebbene sia vero che il danno morale, consistendo nella sofferenza e nel patema d’animo, deve essere
risarcito in misura variabile a seconda, tra gli altri parametri, della maggiore o minore gravità della condotta, si pone
comunque una diseguaglianza.
Infatti, i medici che procurano un danno attenendosi alle linee guida con errore dovuto a colpa lieve avranno diritto
ad una riduzione del risarcimento del danno morale in virtù di tale condotta. Mentre sia i medici che non si attengono
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alle linee guida sia quelli che si trovano a prestare la propria opera in casi in cui non esistono linee guida, dovranno
risarcire integralmente il danno morale nonostante, per ipotesi, la colpa sia lieve in tutti e tre i casi.
Pertanto, la disposizione in esame sembra porre profili di incostituzionalità difficilmente superabili.
Conclusioni
Sulla base di tali rilievi, sembra di poter concludere in senso fortemente dubitativo circa la capacità della riforma di
realizzare i propri obiettivi.
Invero, seppur non fossero accolti gli indicati profili d’incostituzionalità, l’auspicata depenalizzazione della colpa lieve
può facilmente essere evitata estendendo la nozione di colpa grave o comunque sostenendo che attenersi ad una
linea guida a contenuto anche economicistico costituisce colpa grave in quanto la regola base di tutta la professione
medica deve consistere nell’obbligo di fornire in ogni caso il trattamento ottimale.
Comunque, in ambito penalistico, già da anni la gran parte dei procedimenti si chiude con l’archiviazione, ma ciò non
ha né diminuito la spesa sanitaria per pratiche di medicina difensiva né aumentato la serenità dei medici nell’esercizio
della professione.
Anche riguardo all’obbligo risarcitorio, la riforma non sembra poter ridurre le voci di danno risarcibili.
L’unico effettivo risparmio che potrà essere realizzato dalla riforma consiste nella diminuzione dei risarcimenti in virtù
della scelta di applicare anche alla responsabilità medica le tabelle ministeriali relative all’infortunistica stradale.
Ma, poiché tali tabelle riguardano solo le micropermanenti, mentre nella responsabilità medica le invalidità
permanenti superano spesso la soglia del 9%, l’effettivo risparmio di spesa per risarcimenti appare relativamente
poco significativo.
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8. Viganò F. Il medico che si attiene a linee guida e buone pratiche accreditate dalla comunità scientifica non
risponderà più per colpa lieve. Disponibile on line all’indirizzo: http://www.penalecontemporaneo.it/tipologia/0-//-/1831-/ (ultimo accesso il 21-12-2012).
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nuovamente il caso alla Corte d’appello per l’accertamento di merito relativo all’esistenza di linee guida e alla
gravità della colpa.
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pag. 1. Disponibile on line all’indirizzo:
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(ultimo
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20. Cass. civ., Sez. Un., 11 novembre 2008, n. 26972. Disponibile on line all’indirizzo:
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23. Frati P, Montanari Vergallo G, di Luca NM. La riforma del danno alla persona nelle sentenze n. 8827 e 8828/2003
della Suprema Corte. Riv. It. Med. Leg. 2004; 26: 196-223.
24. Castrica F, Farina D, Hemied S, et al. The personal injury compensation in EU law: the attempt at an European
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Autore di riferimento: Gianluca Montanari Vergallo
Dipartimento di Scienze Anatomiche, Istologiche, Medico Legali e dell’Apparato Locomotore,
Corresponding Author: Gianluca Montanari Vergallo
Department of Anatomical, Histological, Medico-Legal and of Locomotive Apparatus Sciences,
“Sapienza” University of Rome, Italy
91
Low embryotoxicity of PEGylated single wall carbon nanotubes
LOW EMBRYOTOXICITY OF PEGYLATED SINGLE WALL
CARBON NANOTUBES
NANOTUBI DI CARBONIO A PARETE SINGOLA FUNZIONALIZZATI CON CATENE PEG
MOSTRANO UN BASSO GRADO DI EMBRIOTOSSICITÀ
Campagnolo L1, Massimiani M1, Aru C1, Palmieri G2, Carrino A1, Mattei M2,
Cecchetti C3,Bergamaschi A4, Sifrani L1, Camaioni A1, Magrini A1, Bottini M3, Pietroiusti A1
1
Department of Biomedicine and Prevention, University of “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy
2
Station for the Animal Technology, University of “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy
3
Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
4
Institute of Occupational Medicine, University Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy
1
Dipartimento di Biomedicina e Prevenzione, Università di “Tor Vergata”, Via Montpellier 1, 00133, Roma
2
Stazione per la Tecnologia Animale, Università di “Tor Vergata”, Via Montpellier 1, 00133, Roma
3
Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
4
Istituto di Medicina del Lavoro, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Roma
Citation: Campagnolo L, Massimiani M, Aru C, et al. Low embryotoxicity of PEGylated single wall carbon nanotubes.
Key words: carbon nanotubes, embryo, embryotoxicity
Parole chiave: nano tubi di carbonio, embrione, embriotossicità
92
Abstract
Nanotechnology, the great revolution of the twenty-first century, consists in the preparation of materials, the
nanoparticles (NP), having at least one of the dimensions below 100 nm (i.e. less than 10-9 meters). The drastic
reduction in size confers to nanoparticles physico-chemical characteristics very different from those of the parent
material, since decreasing the size, the surface to volume ratio considerably increases. This in turn determines that the
majority of the atoms are distributed at the surface of the nanoparticles, thus conferring them a high chemical and
biological reactivity. In the context of
considered one
engineered nanoparticles, the single-walled carbon nanotubes (SWCNT) are
of the most promising materials for applications in both biomedical and industrial fields. There are,
however, indications that the SWCNT can be potentially toxic in some biological contexts. For example, we have recently
shown that certain types of SWCNT, mainly produced for industrial applications, when administered to female mice at an
early stage of pregnancy are capable of inducing fetal malformations of varying severity, up to abortion, in case of
administration at high concentrations.
This observation raises the question about the safety of exposure to this kind of nanoparticles in the workplace during
pregnancy.
In this work, we report some of our subsequent results showing that the addition to the carbon nanotubes of functional
groups consisting of polyethylene glycol chains (PEG-SWCNT) significantly reduces their embryotoxic effect and do not
appear to cause harmful effects in maternal tissues. The functionalization with the polyethylene glycol is, in fact, one of
the methods generally used to increase the biocompatibility of many types of nanoparticles. For our study two different
experimental protocols were adopted: in the first protocol, a group of
pregnant female mice (5.5 day of pregnancy)
have been exposed to the test material with a single dose; in a second group of experiments, females at the same stage
of gestation, received multiple doses up to day 15 of gestation. This second protocol was chosen in order to mimic the
possible daily exposure that a pregnant woman may have in occupational setting. At the end of the experiments the
effects observed both at the level of fetal development and health of the mother's tissues were evaluated for both
groups. Our results showed that the functionalization is actually able to reduce the toxic effect on the fetus, however, we
have observed the occasional appearance of embryos with obvious structural malformations. These observations leave
open the question of safety of exposure to carbon nanotubes in pregnancy, especially at the high doses that can
accidentally occur in the workplace, or in the case of biomedical use of these nanoparticles.
Abstract
Le nanotecnologie rappresentano la grande rivoluzione del XXI secolo. Esse si occupano della preparazione di materiali,
le nanoparticelle (NP), in cui almeno una delle dimensioni sia al di sotto dei 100 nm (ovvero inferiore a 10-9 metri). La
drastica riduzione delle dimensioni conferisce alle nanoparticelle caratteristiche fisico-chimiche molto diverse da quelle
del materiale parentale, e questo perché diminuendo le dimensioni, aumenta considerevolmente il rapporto superficie/
volume. Questo a sua volta determina che la maggior parte degli atomi si vengano a disporre sulla superficie della
nanoparticella, conferendogli una elevata reattività sia chimica sia biologica. Nell’ambito delle nanoparticelle
ingegnerizzate, i nanotubi di carbonio a parete singola (SWCNT) sono considerati uno dei materiali più promettenti per
applicazioni in campo sia biomedico che industriale.
Esistono, tuttavia, indicazioni che i SWCNT possano essere
potenzialmente tossici in alcuni contesti biologici. Per esempio, noi abbiamo recentemente dimostrato che alcuni tipi di
SWCNT, prodotti essenzialmente per applicazioni di tipo industriale, se somministrate a femmine di topo ad uno stadio
iniziale di gravidanza sono in grado di indurre malformazioni fetali di diversa severità, fino all’aborto, nel caso di
somministrazioni a concentrazioni elevate. Questa osservazione apre la questione sulla sicurezza della esposizione in
ambiente lavorativo a questo tipo di nanoparticelle nel corso della gravidanza.
93
In questo lavoro riportiamo alcuni nostri risultati successivi che dimostrano come la aggiunta ai nanotubi di carbonio di
gruppi funzionali costituiti da catene di polietileglicole (PEG –SWCNT) è in grado di ridurre sensibilmente il loro effetto
embriotossico
e di non determinare particolari effetti dannosi a livello strutturale sui tessuti materni. La
funzionalizzazione con il polietilenglicole è, infatti, uno dei sistemi generalmente utilizzati per aumentare la
biocompatibilità di molti tipi di nanoparticelle. Per questo studio sono stati seguiti due diversi protocolli sperimentali: in
un primo caso, un gruppo di femmine (al giorno 5,5 di gravidanza) sono state esposte al materiale in esame una singola
volta, mentre in una seconda serie di esperimenti femmine, allo stesso stadio di gestazione, hanno ricevuto
somministrazioni multiple. Questo secondo protocollo è stato scelto allo scopo di mimare la possibile esposizione
quotidiana che una donna in gravidanza potrebbe avere in ambiente occupazionale. Al termine degli esperimenti sono
stati confrontati gli effetti riscontrati sia a livello dello sviluppo del feto sia della salute dei tessuti della madre. I nostri
risultati hanno mostrato che la funzionalizzazione è effettivamente in grado di ridurre l’effetto tossico sul feto, tuttavia
abbiamo osservato la comparsa occasionale di embrioni con evidenti malformazioni strutturali. Queste osservazioni
lasciano aperta la questione sulla sicurezza della esposizione in gravidanza ai nanotubi di carbonio, sia essa
di tipo
accidentale, come può accadere in ambito lavorativo, sia essa intenzionale, come per esempio nel caso di applicazioni di
tipo biomedico.
Background
The use of nanoparticles for the development of innovative materials represents a real industrial revolution because at
these dimensional levels behaviors and characteristics of matter change drastically and therefore nanotechnologies
represent a radically new way to produce materials, structures and devices with properties and functionality greatly
improved, or entirely new compared to those of the materials composed of the same molecules, but of higher
dimensions.
Responsible development of new materials requires a careful assessment of the risks to health and the environment
associated with the production, use and disposal of these materials.
As the production and applications of nanoparticles are increasing, it is becoming important to determine the impact
and the potential harmful effects of these nanomaterials on human health and the environment before they become in
common use.
Carbon is found in nature in a wide variety of allotropic forms: graphite, diamond, fullerenes, amorphous carbon and
many others. This is due to the properties of the carbon to form different types of bonds, each characterized by a
particular geometry.
Through oxidation and exfoliation, is possible to obtain from graphite the graphene, a material consisting of a layer of
monoatomic carbon atoms. The winding of graphene sheets upon themselves allows to form tubular structures of
nanometric size called nanotubes: the winding of a single layer of grafene allows to obtain single-wall carbon nanotubes
(SWCNTs), while the winding of more layers generates multi-walled nanotubes, MWCNTs.
Carbon nanotubes (CNTs) have an elongated cylindrical structure with diameters of the order of nanometers and lengths
of the order of micrometers: they are considered one of the most promising nanomaterials for different types of
applications, from industrial to biomedical field, thanks to their particular physico-chemical characteristics. For example,
the very high ratio of length to diameter (in the order of 104) allows to consider them as virtually one-dimensional
nanostructures; also, the CNTs are among the strongest materials and rigid in terms of tensile strength and elastic
modulus never discovered before. From an electrical point of view, the CNT have electronic insulating properties,
semiconductive or conductive according to their geometrical structure (1, 2).
Moreover, under certain conditions, the electrons can pass inside a nanotube without heating, making CNTs very
interesting to allow the passage from microelectronics to nanoelectronics; nanotubes are also excellent thermal
conductors along the cylindrical structure, but good insulators laterally to 'axis of the cylinder. In the biomedical field,
CNTs have been used as "drug carrier" for their high load capacity of biomolecules. For example, recently SWCNT
94
conjugates with the chemotherapy agent paclitaxel have been used in vivo to block tumor growth in a mouse model of
breast cancer (3).
Results
To assess whether the conjugation with chains of polyethylene glycol (PEG) was able to reduce or abolish the
embryotoxic effect reported for some types of SWCNT (4), we decorated carbon nanotubes with PEG chains (5), and
studied their ability to induce fetal malformations after intravenous administration to female mice during the first few
days of pregnancy. For this study were used different dosages of nano material, between 10 and 30  g / ml and tested
a number of females equal to or greater than 10 for each group. The presence of fetal and placental abnormalities was
evaluated shortly before delivery, when the process of organogenesis is complete and the fetus is in the growth phase.
We measured the length of the fetuses (crown-rump length, LVS) taken from each of the treated mothers and compared
it with that of control fetuses taken from mothers which received only vehicle (saline). The ability to induce fetal
underdevelopment has been reported for some nanomaterials, such as nanoparticles of silicon and titanium (6). The
administration of these nanoparticles, in a later stage of gestation compared to that provided by our protocol, causes a
significant increase in the number of resorptions and fetal growth retardation and is not associated with changes in the
weight of the placentas (6).
In our conditions, after administration of PEG-CNT, the comparison of the average values of LVS showed no statistically
significant differences between the fetuses of mothers exposed (1.58 ± 0.12) and control groups (1.50 ± 0, 15).
Through use of a dissecting microscope, we then assessed the presence of gross structural malformations and fetal
placenta. In a small number of females who received the highest concentrations of PEG-CNT we observed the presence
of one or more fetuses with obvious abnormal development, associated with alterations of placental cytoarchitecture.
To assess whether the administration of this nanomaterial could affect the health of the mother and hence be reflected
nell'osservata alteration of fetal development, we evaluated some biochemical parameters in maternal blood, such as
ALT, AST, BUN, CREA, LDH and CHO. Comparing the values obtained by mothers of control with those of mothers
treated with the highest concentration of PEG-CNT, none of the analyzed parameters is found to be altered in a
statistically significant manner. These results were further corroborated by histological analysis of the main maternal
tissues (liver, spleen, kidney, lung), which did not reveal the presence of apparent structural alterations.
Discussion and Conclusions
In conclusion, the results of reports indicate that the administration of single-walled carbon nanotubes functionalized
with PEG chains, during the early stages of embryonic development is safe for the mother, but can pose a risk to the
developing fetus, although with a 'low incidence. On the basis of these observations, exposure to PEG-CNT in the
employment and the environment, whether accidental or deliberate, must be strictly monitored. In addition, our results
demonstrate the need to establish in short term measures to regulate occupational exposure of pregnant women.
95
References
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Mintmire JW, Dunlap BI, White CT. Are fullerene tubules metallic?. Phys Rev Lett 1992; 68(5): 631–634.
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Collins PG, Avouris P. Nanotubes for electronics. Sci Am 2000; 283(6): 62-69.
3.
Liu Z, Chen K, Davis C, et al. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res 2008;
68(16): 6652-6660.
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Pietroiusti A, Massimiani M, Fenoglio I, et al. Low doses of pristine and oxidized single-wall carbon nanotubes affect
mammalian embryonic development. ACS Nano 2011; 5(6): 4624-4633.
5.
Delogu LG, Stanford SM, Santelli E, et al. Carbon nanotube-based nanocarriers: the importance of keeping it clean.
J Nanosci Nanotechnol 2010; 10(8): 5293-5301.
6.
Yamashita K, Yoshioka Y, Higashisaka K, et al. Silica and titanium dioxide nanoparticles cause pregnancy
complications in mice. Nat Nanotechnol 2011; 6(5): 321-328.
Corresponding Author: Luisa Campagnolo
Department of Biomedicine and Prevention, University of “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy
Autore di riferimento: Luisa Campagnolo
Dipartimento di Biomedicina e Prevenzione, Università di “Tor Vergata”, Via Montpellier 1, 00133, Roma
96
Resezione loco-regionale endoluminale con tecnica TEM versus Total
Mesorectal Excision per via laparoscopica nel trattamento del cancro
del retto T2 dopo terapia neoadiuvante
RESEZIONE LOCO-REGIONALE ENDOLUMINALE CON TECNICA
TEM VERSUS
TOTAL MESORECTAL EXCISION PER VIA
LAPAROSCOPICA NEL TRATTAMENTO DEL CANCRO DEL RETTO
T2 DOPO TERAPIA NEOADIUVANTE
LOCO-REGIONAL ENDOLUMINAL RESECTION WITH TEM TECHNIQUE VERSUS
TOTAL MESORECTAL EXCISION BY LAPAROSCOPIC IN THE TREATMENT OF RECTAL
CANCER T2 AFTER NEOADJUVANT THERAPY
Paganini AM1, Guerrieri M2, Lezoche G2, Balla A1, Scoglio D1, Quaresima S1, Intini G1,
Antonica M1, Lezoche E1
1
Dipartimento di Chirurgia “Paride Stefanini”, Unità di Chirurgia Endolaparoscopica e Tecnologia Avanzata,
(Direttore Prof. E. Lezoche), Policlinico “Umberto I”, Roma
2
Clinica di Chirurgia Generale e Metodologia Chirurgica, Università Politecnica delle Marche, Ancona
1
Department of Surgery "Paride Stefanini", Endolaparoscopic Surgery and Advanced Technology Unit, (Director Prof.
E. Lezoche), Policlinico "Umberto I", Rome, Italy
2
Clinic of General Surgery and Surgery Methodology, Polytechnic University of Marche, Ancona, Italy
Citation: Paganini AM, Guerrieri M, Lezoche G, et al. Resezione loco-regionale endoluminale con tecnica TEM versus
Total Mesorectal Excision per via laparoscopica nel trattamento del cancro del retto T2 dopo terapia
neoadiuvante. Prevent Res 2013; 3 (2): 97-109. Available from: http://www.preventionandresearch.com/
Parole chiave: cancro del retto, radio chemioterapia neoadiuvante, TEM, TME, ELRR
Key words: rectal cancer, neoadjuvant radiochemotherapy, TEM, TME, ELRR
97
Abstract
Obiettivo dello studio: In pazienti selezionati con cancro del retto basso in stadio non avanzato, l’escissione locoregionale con tecnica TEM associata a terapia neoadiuvante potrebbe essere un’opzione terapeutica alternativa alla Total
Mesorectal Excison (TME).
Metodi: Questo trial randomizzato controllato mette a confronto la Resezione Endoluminale Locoregionale (ELRR)
eseguita mediante la Transanal Endoscopic Microsurgery (TEM) con la TME laparoscopica nel trattamento di pazienti con
cancro del retto distale non avanzato di piccole dimensioni. I pazienti con i seguenti criteri di inclusione: cancro del retto
cT2N0M0, grading istologico G1-2, dimensioni del tumore inferiori ai 3 cm di diametro, margine superiore del tumore
entro 6 cm dal margine anale, sono stati randomizzati verso la ELRR oppure TME laparoscopica. Pazienti ad alto rischio
(ASA III-IV), pazienti con tumore localizzato più cranialmente, scarsamente differenziato (G3) o indifferenziato (G4), o
con invasione linfovascolare e/o perineurale, o di dimensioni maggiori sono stati esclusi.
Tutti pazienti sono stati sottoposti a radio-chemioterapia (RCT) tridimensionale “long-course” a quattro campi in
posizione prona, con preparazione vescicale e uso di contrasto per via endovenosa (14). La dose totale somministrata è
stata di 50,4 Gy in 28 frazioni per cinque settimane. L’area di irradiazione comprendeva: ano, retto, mesoretto, linfondi
regionali ed iliaci. Il limite superiore era a livello di L5-S1, mentre il limite inferiore era a 3-5 cm al di sotto del ramo
ischiopubico. Durante il trattamento radioterapico, è stato somministrato 5-FU in infusione continua alla dose di 200
mg/m2/die.
Risultati: Sono stati analizzati cinquanta pazienti in ogni gruppo. Il tasso complessivo di downstaging e downsizing del
tumore dopo RCT neoadiuvante è stato rispettivamente del 51% e del 26%, ed è risultato simile in entrambi i gruppi.
Tutti i pazienti sono stati sottoposti a resezione R0 con margini di resezione negativi per neoplasia. Al follow-up a lungo
termine quattro pazienti hanno sviluppato recidiva locale (8%) dopo ELRR e tre (6%) dopo TME. Metastasi a distanza
sono state osservate in due pazienti (4%) in ciascun gruppo. Non è stata riscontrata alcuna differenza statisticamente
significativa nella sopravvivenza libera da malattia (P = 0,686).
Discussione e Conclusioni: In pazienti selezionati, la ELRR ha dimostrato risultati oncologici simili alla Total Mesorectal
Excision (TME). L’accuratezza tecnica della ELRR, che può essere raggiunta solo con tecnica TEM effettuata da chirurghi
esperti, permette un trattamento curativo che evita i rischi della chirurgia maggiore, con risultati a breve termine più
favorevoli ed esiti oncologici a lungo termine simili a quelli dopo TME.
Abstract
Aim: Locoregional resection after neoadjuvant therapy may be an alternative treatment option to total mesorectal
excision (TME) in selected patients with non-advanced low rectal cancer.
Methods: In a prospective randomized trial Endoluminal locoregional resection (ELRR) by transanal endoscopic
microsurgery (TEM) was compared to laparoscopic TME for the treatment of patients with early low rectal cancer.
Inclusion criteria were: patients with cT2 N0 M0, G1–2, rectal cancer, tumour diameter less than 3 cm, located within 6
cm from the anal verge. Higher-risk patients (ASA III–IV) with more proximally located tumours, poorly differentiated
(G3) or undifferentiated (G4) tumours, and tumours with lymphovascular or perineural invasion, were excluded.
All patients underwent long-course three-dimensional four-field chemoradiotherapy in the prone position, with bladder
preparation and use of intravenous contrast (14). The total dose given was 50·4 Gy in 28 fractions over 5 weeks. The
irradiated areas were: anus, rectum, mesorectum, and regional and iliac lymph nodes. The superior limit was L5–S1 and
the inferior limit around 3–5 cm under the ischiopubic ramus. A continuous infusion of 5-fluorouracil 200 mg per m2 per
day was administered during radiotherapy treatment.
98
Results: The trial included fifty patients in each group. Tumour downstaging and downsizing rates after neoadjuvant
chemoradiotherapy were 51 and 26 per cent, respectively, and were similar in both groups. R0 resection with tumourfree resection margins was achieved in all patients. Local recurrence developed in four patients (8 per cent) after ELRR
and in three (6 per cent) after TME at long-term follow-up. Distant metastases occurred in two patients (4 per cent) in
each group. No statistically significant difference in disease-free survival was observed(P = 0·686).
Discussion and Conclusions: In selected patients with non-advanced low rectal cancer after neoadjuvant long-course
radiochemotherapy, the oncological results of ELRR by TEM and of TME were similar. The technical accuracy of ELRR,
which can be achieved only by TEM carried out by well trained surgeons, provides a curative treatment that avoids the
risks of major surgery, with more favourable short-term results and similar long-term oncological outcomes to those of
TME.
Introduzione
La microchirurgia endoscopica transanale (TEM) per il trattamento del cancro del retto T1 si è dimostrata essere una
valida alternativa alla chirurgia radicale (1). La maggior parte dei chirurghi, invece, non ritiene sia corretto estendere le
indicazioni della TEM anche al trattamento del cancro del cancro del retto T2. Senza trattamento adiuvante infatti il
tasso di recidiva varia dal 28 al 47% (2, 3, 4 5, 6, 7). È importante notare però che la maggior parte degli studi
pubblicati non fornisce dettagli di tecnica chirurgica sufficienti circa l’ampiezza dell’escissione locale. Il trattamento
neoadiuvante può determinare un “downstaging” della lesione, aumentando la percentuale di conservazione degli sfinteri
oltre a determinare un miglior controllo locale della malattia (8, 9, 10, 11). Il presente studio è stato disegnato per
valutare i risultati oncologici della resezione loco regionale endoluminale (ELRR) eseguita mediante TEM rispetto alla
Total Mesorectal Excision (TME) laparoscopica dopo radio-chemioterapia neoadiuvante in pazienti affetti da cancro del
retto cT2N0M0 e grading istologico G1-2, in termini di recidiva locale e di metastasi a distanza.
Metodi
Questo protocollo è stato definito durante un incontro internazionale di esperti tenutosi ad Urbino nel 1995 ed è stato
approvato dalla commissione etica. I pazienti sono stati arruolati tra l’Aprile 1997 e l’Aprile 2004 nel Dipartimento di
Chirurgica Generale dell’Università di Ancona e nel Dipartimento di Chirurgia Generale, Specialità Chirurgiche e Trapianti
d’Organo “Paride Stefanini” presso l’Università di Roma “La Sapienza”. Questo trial clinico randomizzato ha incluso
pazienti selezionati con tumore del retto distale limitato alla muscolaris propria della parete rettale, senza
lindoadenopatia o malattia metastatica (cT2N0M0) secondo la stadiazione del National Comprehensive Cancer Network
(12). Dopo trattamento neoadiuvante (RCT), i pazienti sono stati sottoposti ad una ri-stadiazione per valutare il grado di
risposta del tumore alla RCT e sono stati successivamente randomizzati nei due bracci dello studio: la ELRR eseguita
mediante TEM oppure la TME per via laparoscopica.
I criteri di inclusione sono stati: American Society of Anesthesiology (ASA) I-II; margine superiore del tumore localizzato
entro 6 cm dal margine anale; adenocarcinoma ben differenziato (G1) o moderatamente differenziato (G2) confermato
istologicamente, di diametro fino a 3 cm.
Pazienti ad alto rischio (ASA III-IV), pazienti con tumore localizzato più cranialmente, scarsamente differenziato (G3) o
indifferenziato (G4), o con invasione linfovascolare e/o perineurale, o di dimensioni maggiori sono stati esclusi.
Stadiazione del tumore all’arruolamento dei pazienti. Per ogni paziente si sono registrate in un database (Microsoft
Excel®; Microsoft, Redmond, Washington, USA) le seguenti informazioni: anamnesi, esami di laboratorio di routine e
dosaggio dei marcatori tumorali, esplorazione rettale per valutare la mobilità del tumore ed il tono dello sfintere, esame
obiettivo.
All’ingresso, la stadiazione è stata effettuata mediante: ultrasonografia endorettale (EUS) (sonda rotante da 7-MHz;
Brüel & Kjaer, Naerum, Denmark); rettoscopia rigida con macrobiopsie del tumore; pancolonscopia e colorazione vitale
del retto, eseguendo 6 - 8 biopsie standard di mucosa normale a circa 1 cm dal margine del tumore (seguite da
tatuaggio con inchiostro India delle sedi delle biopsie); TC spirale Total Body (TC); e risonanza magnetica pelvica (RM).
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La rettoscopia rigida serve a misurare l’esatta distanza del tumore dal margine anale e per determinare la posizione
corretta del paziente sul tavolo operatorio per la procedura chirurgica mediante TEM, che necessariamente deve situarsi
a ore sei nel campo visivo del rettoscopio operatore.
Ogni biopsia è stata esaminata in cieco da tre anatomo-patologi per valutare il grado istologico di differenziazione
cellulare (G1, ben differenziato; G2 moderatamente differenziato; G3, scarsamente differenziato; G4 indifferenziato), e
la presenza di infiltrazione vascolare, linfatica e perineurale.
La positività linfonodale all’imaging è stata stabilita secondo i seguenti criteri: all’EUS, diametro maggiore di 0,8 cm,
forma circolare o irregolare, ipervascolarizzazione all’ Ecocolor-Doppler e ipoecogenicità (13); alla TC e alla RM, diametro
superiore a 0,8 cm, forma circolare o irregolare. Tutti i pazienti con linfonodi sospetti o con risposte contraddittorie alla
stadiazione tumorale mediante EUS, TC o RM sono stati esclusi dallo studio. L’EUS è stata eseguita da operatori esperti
con almeno 5 anni di esperienza. Ogni esame per immagini è stato valutato da due o tre radiologi esperti.
Terapia neoadiuvante. Tutti pazienti sono stati sottoposti a radio-chemioterapia (RCT) tridimensionale “long-course” a
quattro campi in posizione prona, con preparazione vescicale e uso di contrasto per via endovenosa (14). La dose totale
somministrata è stata di 50,4 Gy in 28 frazioni per cinque settimane. L’area di irradiazione comprendeva: ano, retto,
mesoretto, linfondi regionali ed iliaci. Il limite superiore era a livello di L5-S1, mentre il limite inferiore era a 3-5 cm al
di sotto del ramo ischiopubico. Durante il trattamento radioterapico, è stato somministrato 5-FU in infusione continua
alla dose di 200 mg/m2/die.
Stadiazione preoperatoria. Quaranta giorni dopo la fine della RCT, la stadiazione è stata ripetuta come descritto in
precedenza, tranne la colonscopia totale. Lo stesso team chirurgico e radiologico ha rivalutato il paziente per
determinare se si era verificato un “downsizing” o un “downstaging” della lesione. Sulla base della risposta alla RCT, i
pazienti sono stati classificati in “responders” (riduzione della massa tumorale di almeno il 50%) e “low o nonresponders” (riduzione della massa tumorale inferiore al 50%). I pazienti con progressione di malattia sono stati esclusi
dal trial.
Randomizzazione dei pazienti. La randomizzazione è stata eseguita il giorno prima dell’intervento. I pazienti sono stati
allocati casualmente in uguale numero nei due bracci dello studio, ELRR mediante TEM o TME laparoscopica, mediante
buste opache sigillate contenenti un numero generato in modo casuale dal computer. Il reclutamento è stato interrotto
al raggiungimento di 100 pazienti sottoposti ad intervento.
Trattamento chirurgico. Il trattamento chirurgico è stato eseguito tra 45 e 55 giorni dopo la fine della RCT. Tutti i
pazienti sono stati sottoposti a preparazione intestinale con Polietilenglicole e a profilassi antibiotica short-term con
metronidazolo e una cefalosporina di seconda generazione. La procedura chirurgica è stata eseguita da chirurghi esperti
sia in chirurgia a cielo aperto del retto che in entrambe le procedure, sia laparoscopica che TEM. Secondo il protocollo,
ogni chirurgo doveva avere eseguito almeno 80 resezioni laparoscopiche del retto per patologia neoplastica e 100 TEM.
Le tecniche chirurgiche laparoscopiche erano la resezione anteriore o la resezione addomino-perineale sec. Miles con
TME. Queste procedure sono state descritte in dettaglio precedentemente (15).
L’ELRR mediante TEM è stata eseguita con la strumentazione Wolf (Tuttlingen, Germania), come segue. Incisione a tutto
spessore della parete del retto includendo tutta l’area compresa fra i tatuaggi eseguiti all’ammissione del paziente nel
trial, con escissione di almeno 1 cm di mucosa normale intorno al tumore rispetto alle dimensioni della lesione prima
della terapia neoadiuvante. L’incisione della parete del retto veniva condotta in profondità ad includere il mesoretto
adiacente al tumore, seguendo una linea di incisione del grasso perirettale con angolo di circa 120 - 135 gradi rispetto al
piano della mucosa. Per lesioni posteriori e laterali il fondo del piano di dissezione coincideva con la fascia del mesoretto
(cosiddetto “holy plane” di Heald) mentre per le lesioni anteriori coincideva con il setto retto-vaginale o con la capsula
prostatica. Nei tumori con limite distale a livello del canale anale l’incisione includeva la linea dentata e le fibre dello
sfintere interno venivano parzialmente sezionate. La breccia residua veniva chiusa utilizzando una sutura continua,
secondo la tecnica descritta da Buess e Mentges (16).
Endpoints e follow-up. L’endpoint primario di questo studio era la valutazione del risultato oncologico in termini di tassi
di recidiva locale e di metastasi a distanza con un follow-up minimo di almeno 5 anni. L’endpoint secondario era la
valutazione dei risultati a breve termine e in particolare: la mortalità correlata al tumore, il tempo operatorio, le perdite
ematiche, l’uso di antidolorifici, la morbilità, la durata della degenza e la mortalità a 30 giorni. La morbilità maggiore era
definita come le complicanze che richiedevano un trattamento chirurgico. Per valutare la comparsa di recidive locali e/o
sistemiche, tutti i pazienti venivano sottoposti ad una valutazione clinica, dosaggio dei marcatori tumorali e rettoscopia
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ogni 3 mesi per i primi 3 anni, quindi ogni sei mesi. Dal quarto anno in poi gli esami TC total body e RMN pelvica
venivano ripetuti ogni 6 mesi per i primi 5 anni. La terapia adiuvante non è stata utilizzata dopo resezione curativa di
cancro del retto con stadio patologico pT2N0, secondo le linee guida pubblicate in letteratura (12).
Analisi statistica. Usando un log rank test one sided, è stato calcolato che un campione complessivo di 100 pazienti (50
in ogni gruppo) sarebbe stato necessario per raggiungere una forza di circa 80% ad un livello di significatività di 0,05
per rilevare una differenza di 0,20 tra i due gruppi, che rappresenta la probabilità di sviluppare recidive o metastasi a
cinque anni di follow-up (basato su una probabilità di 0,30 nel gruppo della ELRR e di 0,10 nel gruppo della TME).
Un approccio non parametrico è stato usato per analizzare variabili quantitative dal momento che la distribuzione del
campione non era normale. Le variabili quantitative sono presentate come mediana (range interquartile), salvo
diversamente indicato. Il Wilcoxon rank test è stato impiegato per valutare le differenze nei dati continui tra le due
procedure chirurgiche. I dati qualitativi sono stati analizzati mediante il Chi-square test o il Fisher’s Exact Test (se ci si
aspettava una frequenza inferiore a 5).
L’analisi della sopravvivenza è stata applicata per stimare la probabilità cumulativa dello sviluppo di recidive o di
metastasi a distanza come pure per valutare la sopravvivenza complessiva e correlata al cancro. Il metodo Kaplan–Meier
è stato utilizzato per stimare le probabilità cumulative in accordo alla procedura chirurgica e il log rank test per mettere
a confronto le curve risultanti. L’analisi di regressione di Cox è stata eseguita per valutare gli effetti dei fattori
prognostici sulla probabilità di sviluppare i suddetti eventi.
Un livello di probabilità di 0,05 è stato scelto per accertare la significatività statistica ad un intervallo di confidenza del
95% (95% IC).
Tutte le analisi statistiche sono state eseguite utilizzando il software SAS® versione 9.1 (SAS Institute, Cary, North
Carolina, USA).
Risultati
Da una coorte complessiva di 1125 pazienti con cancro del colon-retto osservati dall’Aprile 1997 all’Aprile del 2004, 283
pazienti erano risultati affetti da cancro del retto distale (margine superiore del tumore entro 6 cm dalla rima anale), con
rischio anestesiologico basso (ASA I-II), ed erano pertanto eleggibili per la stadiazione come descritto sopra. I rimanenti
842 pazienti sono stati esclusi per i seguenti motivi: distanza del tumore dal margine anale maggiore di 6 cm, 716
pazienti; ASA III-IV, 87 pazienti; 32 pazienti rifiutavano di far parte dello studio; altre ragioni, 7 pazienti. Di 283
pazienti con cancro del retto distale, 178 non soddisfacevano i criteri di eleggibilità, lasciando quindi 105 pazienti in
stadio cT2N0M0 ammissibili per l’inclusione. Durante la stadiazione preoperatoria tre pazienti hanno rifiutato di aderire al
protocollo e hanno deciso di essere operati altrove. Altri due pazienti, che inizialmente avevano accettato di essere
inclusi nel trial e che erano stati randomizzati per la TME laparoscopica, hanno chiesto invece di essere sottoposti a
chirurgia a cielo aperto. Rimanevano pertanto 50 pazienti per ogni gruppo (Fig. 1). I pazienti dei due gruppi erano simili
in termini di caratteristiche demografiche e risposta al trattamento neoadiuvante (Tabella 1).
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Fig. 1 - Flowchart dello studio, cT, classificazione clinica del tumore; G, grado istologico: ELRR, resezione endoluminale
locoregionale; TEM, microchirurgia endoscopica transanale; TME, total mesorectal excision
Tab. 1 - Caratteristiche principali dei pazienti
Età (Anni)*
Sesso (M:F)
Distanza del margine inferiore
del tumore dal margine anale
(cm)†
Follow-Up (Anni)*
Sopravvivenza al Follow-Up
ELRR (n= 50)
TME (n = 50)
P‡
66 (58-70)
30:20
4,92 (3-6)
66 (60-69)
34:16
5,00 (3-6)
0,899§
0,405
0,716§
9,6 (8,5-11,1)
40
9,6 (7,4-11,9)
43
0,764§
Trattamento Neoadiuvante
Downstaging
0,972
pT0
14 (28)
13 (26)
pT1
12 (24)
12 (24)
pT2
24 (48)
25 (50)
Downsizing nei pT2 (%)
0,879
≥ 50
13 (26)
13 (26)
<50
11 (22)
12 (24)
I valori nelle parentesi sono percentuali a meno che non sia indicato diversamente; i valori sono *mediana (range
interquartile) e †mediana (range). ELRR, resezione endoluminale loco-regionale; TME, total mesorectal excision; pT,
classificazione patologica del tumore. ‡ Test Chi quadro, eccetto § Wilcoxon rank sum test.
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La tossicità da RCT era rappresentata da irritazione della mucosa anorettale e si è verificata in 31 pazienti nel gruppo
ELRR e in 9 pazienti nel gruppo TME. Diarrea si è osservata rispettivamente in 29 e in 11 pazienti. Queste complicanze
sono state risolte con terapia medica e non hanno portato all’interruzione della terapia neoadiuvante.
Il tasso complessivo di “downstaging” e di “downsizing” ottenuto mediante terapia neoadiuvante è stato del 51% e del
26%, rispettivamente. Il tumore ha subito una retrostadiazione in 26 pazienti nel gruppo ELRR (14 pT0, 12 pT1) e in 25
pazienti nel gruppo TME (13 pT0, 12 pT1). Dei restanti 49 pazienti, 26 (13 in ogni gruppo) hanno mostrato una
riduzione del diametro del tumore di più del 50%. Negli altri 23 pazienti si è osservata una riduzione del diametro del
tumore di meno del 50%. Tutti i pazienti arruolati hanno completato la terapia neoadiuvante e nessun paziente ha
mostrato progressione di malattia dopo la stadiazione preoperatoria.
I risultati intraoperatori e postoperatori sono mostrati nella Tabella 2.
Tab. 2 - Principali caratteristiche intraoperatorie e postoperatorie secondo la tecnica chirurgica
ELRR (n = 50)
TME (n = 50)
P†
0 (0)
6 (12)
0,013‡
0 (0)
5 (10)
0,028‡
0 (0)
0 (0)
90 (90-100)
45 (45-45)
0 (0)
7 (14)
11 (22)
12 (24)
174 (160-190)
200 (100-350)
10 (20)
50 (100)
<0,001
<0,001
<0,001§
<0,001§
<0,001
<0,001
3 (3-4)
6 (5-7)
<0,001§
6 (12)
1 (2)
7 (14)
3 (6)
0,766
0,250‡
Cambiamento del programma
intraoperatorio
Conversione in chirurgia a cielo
aperto
Stomia
Temporanea
Definitiva
Durata dell’intervento (min)*
Perdite ematiche (ml)*
N° di pazienti trasfusi
N° di pazienti trattati con
analgesici
Ospedalizzazione (giorni)*
Complicanze postoperatorie
Minori
Maggiori
I valori nelle parentesi sono percentuali a meno che non sia indicato diversamente; i valori sono *mediana (range
interquartile). ELRR, resezione endoluminale locoregionale; TME, total mesorectal excision. ‡ Test Chi quadro, eccetto
‡Fisher’s exact Test e § Wilcoxon rank sum test.
Il tasso di mortalità a 30 giorni è stato zero in entrambi i gruppi. Nessuno dei pazienti trattati con ELRR ha subito una
modifica del programma operatorio, né una conversione dell’intervento a cielo aperto, né una confezionamento di
stomia.
Nel gruppo TME, in sei pazienti (12%) è stato necessario modificare il programma operatorio durante
l’intervento (P=0,013) e l’intervento è stato convertito a cielo aperto in cinque pazienti (10%) (P=0.028). In questo
gruppo 23 pazienti sono stati sottoposti a confezionamento di stomia che è stata temporanea in 11 pazienti (22%), per
proteggere l’anastomosi dopo resezione anteriore ultra bassa, e definitiva in 12 pazienti (24%) che sono stati sottoposti
a resezione addomino-perineale sec. Miles.
Il tempo operatorio è stato significativamente minore nel gruppo ELRR rispetto al gruppo TME (90 contro 174 minuti; P
< 0,001) come pure le perdite ematiche (45 contro 200 ml; P < 0.001). Nessun paziente nel gruppo ELRR ha ricevuto
trasfusioni di sangue, a differenza di 10 pazienti (20%) nel gruppo TME che sono stati sottoposti a emotrasfusione (P <
0,001). Analgesici sono stati somministrati a tutti i pazienti del gruppo TME, ma solo a sette pazienti (14%) del gruppo
ELRR (P < 0,001).
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Dopo ELRR i pazienti hanno potuto assumere liquidi e una dieta semisolida in prima giornata postoperatoria. Nel gruppo
TME, il sondino nasogastrico è stato rimosso alla fine dell’intervento ed i pazienti hanno assunto liquidi per os in prima o
in seconda giornata postoperatoria, ed una dieta semiliquida in terza giornata postoperatoria in funzione della loro
tolleranza. La durata media della degenza è stata di 3 giorni (range 3 – 4 giorni) dopo ELRR e di 6 (5-7) giorni dopo TME
(P < 0,001).
Non ci sono state differenze statisticamente significative tra i due gruppi nel tasso di complicanze postoperatorie minori
o maggiori. Nel gruppo ELRR in sei pazienti (12%) si è osservata una deiscenza della sutura risolta con terapia locale
(clisteri con antibiotici e anestetico locale) e nutrizione parenterale per sei giorni. Una complicanza maggiore, un
flemmone perianale, si è verificato in un paziente diabetico di 68 anni; la colonscopia post operatoria non ha evidenziato
deiscenza della sutura e dopo un tentativo senza successo di trattamento conservativo con terapia antibiotica è stata
eseguita una ileostomia laparoscopica. Nel gruppo TME, in cinque su 38 pazienti (13%) si è osservata una deiscenza
parziale dell’anastomosi, risolta con antibiotici e nutrizione parenterale, e due (4%) hanno avuto una emorragia
postoperatoria trattata con
emotrasfusioni. Tre pazienti con peritonite pelvica da deiscenza anastomotica (8% di 38
pazienti) sono stati trattati con reintervento, toilette peritoneale e ileostomia laparoscopica. La durata media del followup è stata di 9,6 anni per entrambi i gruppi (range 5,5 - 12,4 anni nel gruppo ELRR e 4,7 - 12,3 anni nel gruppo TME).
Tutti i pazienti hanno avuto una resezione R0 con margine di resezione libero da tumore. Nessun linfonodo è risultato
positivo all’istologia definitiva. Il numero medio di linfonodi rimossi con il pezzo operatorio è stato 1 (0 - 3) nel gruppo
ELRR e 11 (10 - 14) nel gruppo TME (P < 0,001). Questo in accordo con il numero medio di linfonodi identificati nel
campione dopo terapia neoadiuvante, che di solito è significativamente inferiore rispetto ai pazienti non sottoposti a RCT
(17).
Durante il follow-up, 6 pazienti hanno sviluppato una recidiva locale o metastasi a distanza dopo ELRR (4 recidiva locale,
2 metastasi a distanza) e 5 dopo TME (3 recidiva locale, 2 metastasi a distanza). In entrambi i gruppi le recidive locali o
le metastasi a distanza si sono verificate solo nei pazienti low o non-responders alla terapia neoadiuvante. La Figura 2
mostra la probabilità cumulativa di sviluppare recidive o metastasi a seconda della procedura chirurgica. La probabilità di
sviluppare recidive o metastasi alla fine del follow-up è stata del 12% (95% I.C. da 6 a 25) dopo ELRR e del 10% (da 4
a 22) dopo TME (P = 0,686).
Dieci pazienti nel gruppo ELRR e 7 nel gruppo TME sono deceduti durante il follow-up. Di questi, 4 e 3 pazienti
rispettivamente sono deceduti per cause cancro-correlate. Il tasso di sopravvivenza cancro-correlata alla fine del followup è stato dell’89% (da 70 a 96) per i pazienti sottoposti a ELRR e del 94% (da 82 a 98) per i pazienti sottoposti a TME
(P = 0,687) (Figura 3). Il tasso di sopravvivenza complessivo alla fine del follow-up è stato del 72% (da 51 a 86) e
dell’80% (da 62 a 90), rispettivamente per la ELRR e per la TME (P = 0,609).
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Fig. 2 - Probabilità cumulativa di sviluppare recidive o metastasi a seconda del tipo di intervento. ELRR, resezione
endoluminale locoregionale; TME total mesorectal excision.
P = 0.686 (log rank test)
Fig. 3 - Probabilità cumulativa di sopravvivenza cancro-correlata secondo il tipo di intervento. ELRR, resezione
endoluminale locoregionale; TME, total mesorectal excision.
P = 0.687 (log rank test)
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L’analisi di regressione di Cox è stata utilizzata per stimare il rischio relativo (RR) del fallimento (sviluppo di recidive,
metastasi e\o morte) in accordo con i fattori prognostici principali. Le variabili incluse nell’analisi sono state: tipo di
procedura (ELRR versus TME), durata dell’intervento, perdite ematiche e degenza postoperatoria. Nel modello finale, il
tipo di procedura (RR 14 - 24, 95% i.c. da 1,36 a 149,16; P = 0,027) e le perdite ematiche (RR 1,01, da 1,00 a 1,01; P
<0,001) sono state le uniche variabili con un effetto significativo sullo sviluppo di recidive o metastasi. Anche se il RR
stimato ha un livello di precisione molto basso per i pochi eventi osservati in entrambi i gruppi (come mostrato
dall’ampiezza dell’intervallo di confidenza), la ELRR ha avuto un ruolo significativo nello sviluppo di recidive o metastasi
a distanza rispetto alla TME. Questo rischio significativamente più alto potrebbe essere spiegato attraverso la più
precoce comparsa di eventi nel gruppo ELRR, come illustrato nella Figura 2. Quando è stato valutato il rischio relativo di
morte, nessuna variabile ha significativamente influito sulla probabilità di fallimento.
Discussione
Secondo quanto riportato in letteratura (1, 18) l’escissione locale è curativa nei pazienti con tumore primitivo limitato
alla mucosa o che invade la sottomucosa del retto, ma senza estendersi oltre questa, in assenza di caratteristiche di
aggressività biologica (scarsa differenziazione, invasione perineurale e linfovascolare, istologia mucinosa e ulcerazione
del tumore), come inoltre dichiarato nelle linee guida per il trattamento del cancro del retto della National
Comprehensive Cancer Network (12).
Pochi studi hanno riportato i risultati dell’escissione locale mediante TEM nel trattamento del cancro del retto T2, ma
questi studi non erano randomizzati e i risultati a lungo termine non sono ancora disponibili (1, 7, 19). Alcuni autori
hanno inoltre riportato risultati oncologici accettabili in pazienti con cancro del retto T3 che hanno risposto alla RCT
neoadiuvante e sono stati trattati mediante escissione trans-anale (8, 9). Questo approccio può avere un risultato
equivalente alla chirurgia radicale nei pazienti che mostrano risposta completa alla RCT neoadiuvante (20). I pazienti
con limitato residuo di malattia dopo RCT hanno un basso rischio di metastasi linfonodali e potrebbero essere idonei per
l’escissione locale (21). Una recente revisione della letteratura ha dimostrato che la risposta patologica completa è
correlata ad un’eccellente sopravvivenza a lungo termine, così come ad un basso tasso di recidiva locale e di metastasi a
distanza (22). La proctectomia con resezione intersfinterica ed escissione locale è una alternativa alla resezione
addomino-perineale che ha mostrato risultati oncologici accettabili con un migliore esito funzionale rispetto alla chirurgia
radicale (23), sebbene non sempre soddisfacente.
Gli autori hanno descritto la ELRR, una tecnica chirurgica originale che comprende la resezione en bloc della parete del
retto, del grasso mesorettale loco-regionale e della sua fascia. Questo studio è stato disegnato come un trial prospettico
randomizzato che mette a confronto i risultati a breve e lungo termine (follow-up minimo cinque anni) di due procedure
chirurgiche mini-invasive ( ELRR mediante TEM versus la TME laparoscopica con resezione anteriore bassa o resezione
addomino-perineale) per cancro del retto di piccole dimensioni cT2N0M0, G1-2, trattato precedentemente con RCT
“long-course”.
Uno stretto follow-up è essenziale per identificare i casi in cui è necessaria una chirurgia di salvataggio. Nel trattamento
del cancro del retto distale, il problema maggiore dopo TME è la recidiva locale che comporta una prognosi infausta (24).
In questi casi un trattamento curativo con conservazione degli sfinteri è raramente possibile. Al contrario, una recidiva
locale della mucosa che si sviluppi dopo ELRR mediante TEM può essere trattata attraverso TME di salvataggio (25).
La terapia neoadiuvante può determinare un “downstaging” o un “downsizing” del tumore, può ridurre il tasso di recidiva
locale e aumentare il tasso di conservazione dello sfintere (11, 26). La RCT preoperatoria è stata ben tollerata dai
pazienti e nell’esperienza degli autori non ha incrementato significativamente né le difficoltà tecniche dell’intervento né il
rischio di deiscenza della sutura durante la resezione laparoscopica o la TEM. La critica principale all’escissione locale è
che essa non asporta le stazioni linfonodali drenanti. Una corretta stadiazione mediante “imaging” prima della terapia
neoadiuvante è cruciale per definire l’eleggibilità dei pazienti candidati a ELRR. In questo studio, tutti i pazienti sono stati
sottoposti a risonanza magnetica pelvica e a TC total-body prima della chirurgia, esaminate da due o tre operatori
differenti, e a ecografia transrettale al fine di valutare il parametro T, lo stato dei linfonodi e identificare una eventuale
patologia metastatica.
La maggior parte degli studi pubblicati sull’escissione locale non ha descritto in maniera sufficientemente chiara la
tecnica chirurgica utilizzata per poter valutare se l’escissione locale eseguita sia stata adeguata in termini di clearance
dei margini circonferenziale e radiale del tumore, così come la profondità di escissione del grasso mesorettale. In uno
106
studio multicentrico sulla escissione locale mediante TEM condotto su 847 pazienti, è stato riportato un tasso di recidiva
locale del 29,3% (27). Ci sono molte ragioni per questi risultati sfavorevoli: il numero limitato di pazienti arruolati da
ciascun centro, una stadiazione preoperatoria inadeguata (nel 31% dei pazienti la lesione era considerata benigna) e la
tecnica chirurgica (tasso di resezioni R1 del 22%). Inoltre solo il 34,3% delle resezioni TEM di questo studio (27) ha
aderito alle linee guida internazionali approvate per l’escissione locale. L’estensione della rimozione del mesoretto en
bloc insieme alla parete rettale è l’innovazione chirurgica più rilevante che differenzia la tecnica chirurgica impiegata nel
presente studio rispetto a quella di altri autori (16).
I risultati oncologici di questo studio hanno mostrato che la probabilità di sviluppare recidive o metastasi a distanza è
stata simile in entrambi i gruppi. Inoltre, il tasso di sopravvivenza cancro-correlata alla
fine del follow-up non ha
mostrato differenze. I risultati a breve termine, d’altro canto, favoriscono in maniera significativa la ELRR
mediante
TEM, in termini di tempo operatorio, tasso di confezionamento di stomia, perdite ematiche e trasfusioni, uso di farmaci
analgesici e durata della degenza. Non ci sono state differenze significative in termini di morbilità, sebbene dopo la TME
siano state osservate un maggior numero di complicanze sia maggiori che minori, come peritonite pelvica ed emorragia.
Al contrario, non si è verificata alcuna complicanza quod vitam dopo la ELRR mediante TEM, e non si è osservata
deiscenza della linea di sutura nell’unico paziente di questo gruppo sottoposto ad ileostomia, il quale era affetto da
diabete mellito.
In un precedente studio, gli autori hanno riportato che il grado istologico, considerato tradizionalmente un valido fattore
prognostico, è sembrato meno determinante nel predire i risultati dopo RCT neoadiuvante (26). Su queste basi si
raccomanda una durata più lunga del follow-up, come riportato in questo studio.
Conclusione
La ELRR mediante TEM può essere impiegata nel trattamento di pazienti con cancro del retto cT2N0M0 di ridotte
dimensioni dopo RCT neoadiuvante. La corretta selezione dei pazienti è un fattore cruciale e richiede un team
multidisciplinare dedicato. L’accuratezza tecnica della ELRR, che può essere raggiunta solo con tecnica TEM effettuata da
chirurghi esperti, permette un trattamento curativo che evita i rischi della chirurgia maggiore, con risultati a breve
termine più favorevoli ed esiti oncologici a lungo termine simili a quelli dopo TME.
107
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108
25. Bretagnol F, Merrie A, George B et al. Local excision of rectal tumours by transanal endoscopic microsurgery. Br J
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Microsurgery (TEM) Collaboration. A predictive model for local recurrence after transanal endoscopic microsurgery
for rectal cancer. Br J Surg 2009; 96: 280–290.
Autore di riferimento: Andrea Balla
Corresponding Author: Andrea Balla
Department of Surgery "Paride Stefanini", Endolaparoscopic Surgery and Advanced Technology Unit,
(Director Prof. E. Lezoche), Policlinico "Umberto I", Rome, Italy
109
THE PRIMARY AND SECONDARY ENDOMETRIOSIS WITHIN
ABDOMINAL WALL
ENDOMETRIOSI PRIMARIA E SECONDARIA DELLA PARETE ADDOMINALE
Capoano R1, Tesori MC1, Mastroluca E1, Lacroce G1, Police A1, Llange K1, Gianfrancesco E1,
Donello C1, Lombardo F1, Salvati B1
1
1
Department of Surgical Sciences, “Sapienza” University of Rome, Italy
Dipartimento di Scienze Chirurgiche, “Sapienza” Università di Roma
Citation: Capoano R, Tesori MC, Mastroluca E, et al. The primary and secondary endometriosis within abdominal wall.
Key words: endometriosis, abdominal wall, surgery
Parole chiave: endometriosi, parete addominale, chirurgia
Abstract
Background: Endometriosis is defined as the presence of functional endometrial glands and stroma outside the uterine
cavity. It’s classified in primary and secondary forms. The endometriosis is a common gynecological disease with an
estimated prevalence of 8-15%, usually occurs in women during the reproductive years, with the maximum incidence
being between the ages of 30 and 40 years.
The primary form of the rectus abdominis muscle includes lesions that were not a result of a previous surgical procedure
and this is an exceptional occurrence and only 18 cases have been described in the literature from 1984 to 2004. The
incidence of the secondary form has been estimated to 0,003%-4%.
Cases: We report a rare case of primary endometrios, a case of endometrios in the inguinal area and a case of scar
endometriosis. In two cases the treatment of choice was the surgical excision that should include 5-10 mm of
surrounding healthy tissue; in the third case during operative dissection for hernia was found the presence of a hard
granulomatous lesion that was removed. Follow-up was performed by subjecting the patients to a transvaginal and trans
abdominal ultrasonography, detection of serum level of CA-125 and a gynaecological evaluation 6 months after surgery.
An MRI scan was performed 1 year after surgery. All tests gave negative results.
Discussion: The causes of endometriosis is unknown, but there are several theories. The most popular is the retrograde
menstruation, proposed by Sampson. A second theory is the vascular-lymphatic dissemination can explain occurrence of
endometriosis in such distant sites. A third theory is coelomic metaplasia, this would explain endometriosis in the
110
postmenopausal women and in the male patient who is undergoing estrogen therapy for prostatic carcinoma. The
symptoms of the disease are cyclic or catamenial pain associated with a palpable mass. The differential diagnosis
includes: hernia, hematoma, lymphoadenopaty, lymphoma, lipoma, abscess, subcutaneous cyst, neuroma and desmoids
tumor. The serum level of CA-125 can be slightly increased. Additional studies of ultrasound, FNA (Fine-needle aspiration
cytology), CT scan or MRI scan may be needed for the final diagnosis. FNA has been used in the preoperative
assessment of abdominal wall masses, has been reported to be useful in excluding the possibility of malignancy, but
seems to be inconclusive in formulating diagnosis and has been associated to an increased risk of recurrence. MRI may
show characteristic findings due to iron in the hemosiderin deposit6s in an endometrioma. The treatment of choice is a
surgical wide excision.
Conclusions: The treatment of choice is a surgical wide excision with clear margins, that is decisive as demonstrated by
follow-up. Recurrence is rare , usually presents within 1 year and is likely to be the result of an inadequate excision.
Medical treatment of abdominal wall endometriosis is usually unsuccessful.
Abstract
Introduzione: L’endometriosi viene definita come la presenza anomala di tessuto ghiandolare e stromale endometriale
ormono-responsivo al di fuori della cavità uterina. Viene classificata in primaria e secondaria (su cicatrice chirurgica da
pregresso intervento sulla cavità uterina). L'endometriosi è una patologia che interessa donne in età riproduttiva con la
massima incidenza tra i 30 ed i 40 anni, la cui prevalenza è stimata pari al 8-15%. L’impianto extrapelvico può
interessare vari organi e la localizzazione a livello della parete addominale è rara (0,03%-1%). La localizzazione primaria
in corrispondenza dei muscoli retti dell’addome è evenienza estremamente rara, descritta in Letteratura in 18 casi ed il
primo a descriverla fu M. Amato nel 1984.
Casi clinici: Descriviamo i casi di nostra osservazione: un caso di endometriosi primaria, un caso di endometriosi su
Pfannensteil ed un caso di endometrioma in regione inguinale. In due pazienti il trattamento di escissione della
formazione, con margine di tessuto sano di 5-10 mm è stato di scelta; nel terzo la formazione dura e granulomatosa è
stata asportata nel corso dell'intervento chirurgico condotto per la presenza di un'ernia inguinale. Tutte le pazienti sono
state sottoposte nel follow-up a valutazione dei livelli sierici di CA 125, visita ginecologica a 6 e 12 mesi e RMN di
controllo ad un anno. Nessuna complicanza e nessun caso di recidiva, con negativizzazione dei livelli del marcatore.
Discussione: La causa rimane sconosciuta: la prima ipotesi proposta da Sampson la attribuisce ad una mestruazione
retrograda; la seconda ad una disseminazione linfo-vascolare che giustificherebbe l’impianto in siti distanti; la terza
indica come possibile responsabile una metaplasia celomatica. Il sospetto diagnostico è fornito da un'attenta anamnesi e
la diagnosi differenziale include tipologie diverse di tumefazioni: ernia, formazioni cistiche, ematomi, sieromi, ascessi,
tumore desmoide, neurinoma, linfadenopatia, linfoma. Importante è la valutazione dei livelli sierici del CA 125 che
risultano di solito elevati. E’ necessario un approfondimento diagnostico con: ecografia, TC o RMN, F.N.A.B. L’agoaspirato è una metodica scarsamente sensibile, associata ad un aumento del rischio di recidive. La risonanza magnetica
riesce ad evidenziare il Ferro presente all’ interno dei depositi di emosiderina caratteristici dell’endometrioma. Il
trattamento in ogni caso è quindi chirurgico.
Conclusioni: La diagnosi di certezza, ad oggi, è solo istologica ed il trattamento di scelta non può quindi essere che
l'asportazione chirurgica. Le recidive sono rare, di solito si presentano entro il primo anno dovute, nella maggior parte
dei casi, ad un’inadeguata escissione.
Background
Endometriosis is defined as the presence of functional endometrial glands and stroma outside the uterine cavity (1),
indeed this condition is not present before the menarche. It’s classified in primary and secondary form. The primary
form of the rectus abdominis muscle includes lesions that were not a result of a previous surgical procedure and this is
111
an exceptional occurrence and only 18 cases have been described in the literature from 1984 to 2004 (2, 3). The
incidence of the secondary form has been estimated to 0,003%-4% (4). We report a very rare case of primary
endometriosis of the rectus abdominis muscle and two cases of secondary endometriosis.
Case I
A 30-years old woman came to our observation reporting the presence a neoformation of two centimetres in diameter to
the right rectus abdominis muscle. Her personal history for previous surgery and for pelvic endometriosis was negative.
The patient did not link the unsteady nature of the periodic exacerbation of the pain flowed by total pain remittance,
with her menstruation. Clinical examination showed a neoformation of two centimetres in diameter of tense-elastic
consistency immobile, aching to the touch. There was evidence to support the possibility of a soft tissue neoplastic
growth. The patient’s laboratory results (general blood count and serum level of CA-125 and CA-19,9) were all within
the normal range. The patient was subjected to ultrasound transvaginal that was negative for the pelvic or ovarian
endometriosis and to ultrasound trans-abdominal that was confirmed the presence of the neoformation. The surgical
removal of the lesion, wich showed the relantionship with deep subcoutaneus tissue and the right rectus abdominis
muscle, was performed. No connection with intra-abdominal structures was indentified. The istological examination
showed the presence of endomediotric tissue within the fibro-adipose and muscle tissue. Currently, the patient, without
any medical treatment is in a follow-up for 5 years with negative results for recovery of the disease.
Case II
A 31-years old woman came to our observation reporting the presence of a mass of 3 centimeters in diameter at the
midline of a pfannensteil incision. She had a typical Pfannensteil skin incision having healed normal after having a child
birth 3 years before admission. The patient reported that the neoformation increased in size and appeared to fluctuate in
size with relation to her menstrual periods. The pain was a periodic abdominal scar pain associated with menses. Her
personal history was negative for pelvic endometriosis and the patient’s laboratory results (CA -125) were all within the
normal range. The patient was subjected to clinical examination that confirmed the presence of neofomation of tenseelastic consistency, aching to the touch. The ultrasound transabdominal showed a neoformation. The mass was excised
en–block. Macroscopically the lesion
appear as characteristic “chocolate cysts”. The histology report concerned a
specimen 3x2.5 cm in dimension; within this tissue specimen multiple sites of endometriosis was revealed. The patient
was followed up 5 months post-operatively and did not was found evidence of recurrence.
Case III
A 36 years-old woman came to our observation for evaluation of a bulge in her right groin. The patient reported that the
bulge had been present for approximately 6 months and increased in size with relation to her menstrual periods. The
clinical examination showed a tender mass at the left corner of Pfannensteil incision, two centimeters above Poupart’s
ligament, immobile, irreducible. The patient had no history of pelvic endometriosis. The pre-operative diagnosis was a
femoral hernia. During operative dissection hernia was found and the operative tilted towards the existence of a hard
granulomatous lesion. The istological examination showed the presence of endometriosis.
Discussion
Endometriosis is a common gynecological disease with an estimated prevalence of 8-15% (5), usually occurs in women
during the reproductive years, with the maximum incidence being between the ages of 30 and 40 years (6). There are
however reported rare cases in postmenopausal (7) women and in men (8). Endometriosis, first described by
Rokintansky in 1860 (9), is defined as the presence of functioning endometrial tissue in anatomic locations other than
the uterine cavity. The finding of ectopic endometrial tissue within the abdominal wall seems to occur among 0,03% to
1% (4) of women who have undergone prior gynaecologic or obstetric surgery. Endometrial lesions, solely confined to
within the body of the rectus abdominis muscle are an exceptional occurrence and to date in the Literature only 18
cases, the first was described in 1984 by Amato and Levitt (10). The causes of endometriosis is unknown, but there are
several theories. The most popular is the retrograde menstruation, proposed by Sampson. A second theory is the
vascular-lymphatic dissemination, can explain occurrence of endometriosis in such distant sites. A third theory is
coelomic metaplasia, this would explain endometriosis in the postmenopausal women and in the male patient who is
undergoing estrogen therapy for prostatic carcinoma. The symptoms of the disease are cyclic or catamenial pain
112
associated with a palpable mass. The differential diagnosis includes: hernia, hematoma, lymphoadenopaty, lymphoma,
lipoma, abscess, subcutaneous cyst, neuroma and desmoids tumor. The serum level of CA-125 can be slightly increased
(11). Macroscopically, pelvic or intrabdominal lesions appear as characteristic redish-blue implants or “chocolate cysts”.
Depending on the extent of intralesional hemorrhage, nodules may be of two types: (1) primarily composed of glands
and hemosiderin-laden histiocytes or (2) solid rubbery mass , wich contain an abundance of granulation tissue (10).
Additional studies of ultrasound, FNA (Fine-needle aspiration cytology), CT scan or MRI scan may be needed for the final
diagnosis. FNA has been used in the preoperative assessment of abdominal wall masses, has been reported to be useful
in excluding the possibility of malignancy, but seems to be inconclusive (12) in formulating diagnosis and has been
associated to an increased risk of recurrence (12). MRI may show characteristic findings due to iron in the hemosiderin
deposit6s in an endometrioma (13). The treatment of choice is a surgical wide excision.
We report a rare case of primary endometrios, a case of endometrios in the inguinal area and a case of scar
endometriosis. In two cases the treatment of choice was the surgical excision that should include 5-10 mm of
surrounding healthy tissue; in the third case during operative dissection no hernia was found but the presence of a hard
granulomatous lesion that was removed. Follow-up was performed by subjecting the patients to a transvaginal and trans
abdominal ultrasonography, detection of serum level of CA-125 and a gynaecological evaluation 6 months after surgery.
An MRI scan was performed 1 year after surgery. All tests cave negative results. Our patients has been subjected only
to the surgery with a wide local excision of the lesion with negative margins, without any medical treatment.
Conclusions
The treatment of choice is a surgical wide excision with clear margins, that is decisive as demonstrated by follow-up.
Recurrence is rare , usually presents within 1 year and is likely to be the result of an inadequate excision. Medical
treatment of abdominal wall endometriosis is usually unsuccessful.
113
References
1. Blaustein A. Pelvic Endometriosis. In Blaustein A. Pfemale genital tract. Second edition. Spring Velag, New York,
1982.
2. Coley BD, Casola G. Incisional endometrioma involving the rectus abdominis muscle and subcutaneous tissues: CT
appearance. AJR Am J Roentgenol 1993; 160: 549–550.
3. Feeney J, Govender P, Snow A, Torreggiani WC. Answer to case of the month#136. Endometrioma of the rectus
sheath after Caesarean section. Can Assoc Radiol J 2008; 59: 210–212.
4. Randriamarolahy A, Perrin H, Cucchi JM, et al. Endometriosis following cesarean section: ultrasonography and
magnetic resonance imaging. Clinical Imaging 2010; 34:113–115.
5. Horton JD, Dezee KJ, Ahnfeldt EP, Wagner M. Abdominal wall endometriosis: A surgeon’s perspective and review of
445 cases. Am J Surg 2008; 196: 207–212.
6.NikkanenV, Punnonen R. External endometriosisin 801 operated patients. Acta Obstet Gynecol Scand 1984; 63: 699701.
7. Molgaard CA, Golbeck AL, Gresham L. Current concepts of endometriosis. West J Med 1985; 143; 42-46.
8. Michowitz M, Baratz M, Stavorovsky M. Endometriosis of the umbilicus. Dermatologica 1983;167:326-330.
9. Molgaard CA, Golbeck AL, Gresham L. Current concepts of endometriosis. West J Med 1983; 143:42-46.
10. Amato M, Levitt R. Abdominal wall endometrioma: CT findings. J Comput Assist Tomogr 1984; 8: 1213–1214.
11. Luisi S, Gabbanini M, Sollazzi S, et al. Surgical scar endometriosis after Cesarean section. A case report. Gynecol
Endocrinol 2006; 22 :284-285.
12.Bumpers HL, Butler KL, Best IM. Endometrioma pf the abdominal wall. Am J Obstet Gynecol 2002;187:1709-1711.
13.Huff TN, Geiger XJ, Duffy GP, O’Connor MI. Case report: Endometrioma of the abdominal wall. Clin Orthop Relat Res
2007; 463: 221–224.
Corresponding Author: Raffaele Capoano
Department of Surgical Sciences, “Sapienza” University of Rome, Italy
Autore di riferimento: Raffaele Capoano
Dipartimento di Scienze Chirurgiche, “Sapienza” Università di Roma
114
TRATTAMENTO MINI INVASIVO DELLA FISTOLA
RETTO-VAGINALE
MINI-INVASIVE TREATMENT OF RECTOVAGINAL FISTULA
D’Ambrosio G1, Paganini AM1, Guerrieri M2, Lezoche G2, Balla A1, Quaresima S1, Scoglio D1,
Antonica M1, Intini G1, Mattei F1, Lezoche E1
1
2
Clinica di Chirurgia Generale e Metodologia Chirurgica, Università Politecnica delle Marche, Ancona
1
Department of Surgery "Paride Stefanini", Endolaparoscopic Surgery and Advanced Technology Unit, (Director Prof.
E. Lezoche), Policlinico "Umberto I", Rome, Italy
2
Clinic of General Surgery and Surgery Methodology, Polytechnic University of Marche, Ancona, Italy
Citation: D’Ambrosio G, Paganini AM, Guerrieri M, et al. Trattamento mini invasivo della fistola retto-vaginale.
Parole chiave: fistola retto-vaginale, TEM, trattamento chirurgico
Key words: recto-vaginal fistula, TEM, surgical treatment
115
Abstract
Introduzione: Le fistole retto-vaginali (RVF) sono una patologia rara di interesse chirurgico. La causa più comune è una
lesione ostetrica. Altre cause frequenti sono le malattie criptoghiandolari, le malattie infiammatorie intestinali, la
radioterapia pelvica, e la chirurgia del colon-retto correlata a una guarigione parziale di un’anastomosi colorettale o un
precedente ascesso. La guarigione spontanea è estremamente rara. Tale guarigione si verifica raramente anche dopo
confezionamento di una stomia derivativa. Il loro trattamento è estremamente difficile, e non vi è a tutt’oggi una tecnica
chirurgica standard universalmente accettata. Gli approcci chirurgici riportati per il trattamento delle fistole rettovaginali sono transanale, transvaginale, perineale, transaddominale, e tecniche laparoscopiche. Questo report descrive
un nuovo approccio al trattamento delle fistole retto-vaginali mediante la microchirurgia endoscopica transanale (TEM).
Metodi: E’ stata condotta una review retrospettiva di 13 pazienti (età media, 44 anni range 25-70 anni) sottoposti a
riparazione di fistola retto-vaginale con TEM tra il 2001 e il 2008. In nove casi, le fistole retto-vaginali erano già state
trattate altrove con una sutura transperineale diretta delle pareti rettali e vaginali e quattro pazienti erano state
sottoposte a due o tre precedenti tentativi di riparazione chirurgica con approccio transaddominale o transperineale, o
entrambi, e la sutura diretta. Tutte le pazienti erano portatrici di stomia derivativa quando sono giunte alla nostra
osservazione. Le fistole si sono verificate come conseguenza di un intervento di isterectomia transvaginale (N=7), di
resezione anteriore bassa con suturatrice meccanica (n=5) e postradioterapia (n=1). La tecnica chirurgica è stata
ampiamente descritta, ed i vantaggi dell’approccio endorettale sono noti. L'uso della TEM segue gli stessi principi della
chirurgia tradizionale, con i noti vantaggi relativi alla magnificazione della visione e dell’illuminazione. La paziente viene
posta in posizione prona sul tavolo operatorio.
Risultati: Il tempo operatorio medio è stato di 130 minuti (range 90-150 minuti), e la degenza in ospedale è stata di 5
giorni (range, 3-8 giorni). Una sola paziente ha presentato recidiva di malattia. Questa paziente è stata sottoposta ad un
secondo intervento di TEM e ha presentato nuovamente una recidiva. Due pazienti hanno avuto complicanze minori
(ematoma del setto e ascesso del setto) che sono state trattate con terapia medica. In due pazienti, si è registrata una
modesta ipotonia dello sfintere.
Discussione e Conclusioni: Presentiamo una nuova tecnica per il trattamento delle fistole retto vaginali con TEM. Gli
autori raccomandano caldamente questo approccio che evita qualsiasi incisione della zona perineale,che può risultare
estremamente dolorosa e può danneggiare la funzione sfinteriale.
Abstract
Background: Rectovaginal fistulas (RVFs) are a rare surgical condition. Obstetric injury is the most common cause.
Other more frequent causes are cryptoglandular disease, inflammatory bowel disease, pelvic radiotherapy, and
colorectal surgery related to partial healing of colorectal anastomosis or previous abscess. Spontaneous healing is
extremely rare. Such healing also rarely occurs after stoma. Their treatment is extremely difficult, and no standard
surgical technique is accepted worldwide. Various surgical and nonsurgical methods of repair are used, and a gold
standard procedure still is to be determined. The surgical approaches reported for the treatment of high RVF are
transanal, transvaginal, perineal, transabdominal, and laparoscopic techniques of repair. This report describes a new
approach using Transanal Endoscopic Microsurgery (TEM) to treat RVFs.
Methods: A retrospective review of 13 patients (median age, 44 years; range, 25–70) who underwent repair of
rectovaginal fistula using TEM between 2001 and 2008 was undertaken. In nine cases, RVFs were first treated elsewhere
with transperineal direct suture of the rectal and vaginal walls, and four patients had two or three previous attempts at
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surgical repair with the transabdominal or transperineal approach or both and direct suture. All the patients had a
diverting stoma at the first referral. Fistulas occurred as a consequence of transvaginal hysterectomy (n = 7), low
anterior mechanical resection (n = 5), and postradiotherapy (n = 1). The surgical technique is widely described. The use
of TEM follows the same principles as traditional surgery, with the well-known advantages related to magnification of the
view and excellent lightning. The patient is placed in prone position on the operating table.
Results: The median follow-up period was 25 months, and the median age of the patients was 44 years (range, 25-70
years). The mean operative time was 130 min (range, 90-150 min), and the hospital stay was 5 days (range, 3-8 days).
One patient experienced recurrence. This patient underwent reoperation with TEM and experienced re-recurrence. Two
patients had minor complications (hematoma of the septum and abscess of the septum), which were treated with
medical therapy. For two patients, a moderate sphincter hypotonia was registered.
Discussion and Conclusions: A new technique for treating RVFs using TEM is presented. The authors strongly
recommend this approach that avoids any incision of the perineal area, which is very painful and can damage sphincter
functions.
Introduzione
Le fistole retto-vaginali rappresentano una patologia chirurgica estremamente dolorosa ed invalidante a livello fisico,
psicologico e sociale per le donne che ne sono affette. L’imbarazzo e l’isolamento per la propria condizione sono
comunemente sperimentati da queste donne. La causa più comune è una lesione ostetrica. Altre cause frequenti sono
le malattie criptoghiandolari, le malattie infiammatorie intestinali, la radioterapia pelvica, e la chirurgia del colon-retto
correlata a una guarigione parziale di un’anastomosi colorettale o un precedente ascesso. La guarigione spontanea è
estremamente rara. Tale guarigione si verifica raramente anche dopo confezionamento di una stomia derivativa.
Il trattamento delle fistole retto-vaginali è considerato estremamente complesso e sono state proposte varie tecniche. La
riparazione primaria della fistola ha un tasso di successo del 70-97%, tuttavia a seguito di uno o più tentativi di
riparazione il tasso di successo scende al 40-85% (1). Per la riparazione sono state utilizzate varie tecniche, chirurgiche
e non, nonostante non sia stata ancora determinata la procedura “gold standard”. Gli approcci chirurgici riportati per il
trattamento
delle
fistole retto-vaginali
sono
transanale, transvaginale,
perineale,
transaddominale,
e
tecniche
laparoscopiche (2). La procedura più comunemente utilizzata è la riparazione della mucosa rettale con lembo
di scorrimento con percentuali di successo che vanno dal 60-80%. Gli approcci non chirurgici sono la fistolografia e
l’applicazione di colla di fibrina.
Questo studio mira a descrivere un nuovo approccio che gli autori hanno sviluppato, che impiega la Transanal
Endoscopic Microsurgery (TEM) per rimuovere la fistola e il tessuto cicatriziale circostante.
Materiali and metodi
Dal febbraio 2001 al dicembre 2008, sono state trattate 13 pazienti (età media, 44 anni, range 25-70) con fistola rettovaginale. In nove casi, le fistole retto-vaginali erano già state trattate altrove con una sutura transperineale diretta delle
pareti rettali e vaginali e quattro pazienti erano state sottoposte a due o tre precedenti tentativi di riparazione
chirurgica con approccio transaddominale o transperineale, o entrambi, e la sutura diretta. Tutte le pazienti erano
portatrici di stomia derivativa quando sono giunte alla nostra osservazione. Le fistole si sono verificate come
conseguenza di un intervento di isterectomia transvaginale (N=7),
di resezione anteriore bassa con suturatrice
meccanica (n=5) e postradioterapia (n=1).
L'algoritmo preoperatorio per tutti i pazienti includeva la colonscopia, il clisma a raggi X, l’ecografia transrettale,
la manometria anorettale e la tomografia computerizzata (TC), o la risonanza magnetica nucleare (RMN). La
117
preparazione preoperatoria consisteva in una irrigazione meccanica standard dell’intestino, una profilassi antibiotica
e trombotica. La distanza media delle fistole retto-vaginali dal margine anale era di 7 cm (range 4-10 cm).
L'uso della TEM segue gli stessi principi della chirurgia tradizionale, con i noti vantaggi relativi alla magnificazione della
visione e dell’illuminazione. La paziente viene posta in posizione prona sul tavolo operatorio. L'intervento segue quattro
fasi:
Fase 1. Viene introdotto il rettoscopio di Buess, viene chiaramente identificata la fistola introducendo un tubo di Nelaton
attraverso la vagina o mediante l’iniezione del blu di metilene. La vagina viene poi tamponata con delle garze per evitare
o ridurre la dispersione di anidride carbonica (CO2) (Figura. 1).
Fig. 1 - Identificazione della fistola
Fase 2. Sotto visione tridimensionale diretta della TEM, il tessuto sclerotico della fistola viene ampiamente asportato. Il
margine della linea di escissione dovrebbe essere su tessuto sano. Un approccio conservativo rischia di non includere
tutto il tessuto cicatriziale e può portare a risultati non soddisfacenti. La dissezione del setto retto-vaginale lateralmente
e in senso aborale della fistola può essere facilmente eseguita con la strumentazione TEM. Quando la dissezione
del setto è completata, la strumentazione TEM viene temporaneamente rimossa.
Fase 3. Dopo aver introdotto il dito nella zona di dissezione del setto, il chirurgo completa alla cieca la dissezione della
parte aborale del setto finché non raggiunge le fibre dello sfintere (la parte orale del setto è stata precedentemente
preparata con TEM). Questa parte dell'operazione non può essere effettuata utilizzando la strumentazione TEM per
ragioni tecniche. Una volta identificato il piano corretto la dissezione di questa parte del setto è facile e non ha alcun
rischio di sanguinamento (Figura. 2).
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Fig. 2 - Dissezione del setto
Fase 4. Il rettoscopio di Buess viene introdotto di nuovo, il bordo della vagina viene suturato con tre o quattro punti per
ottenere una sutura longitudinale. L’estremità dei punti di sutura viene lasciata all’interno del canale vaginale per essere
legata alla fine dell'intervento. L'emostasi viene accuratamente revisionata, e si esegue una linea di sutura trasversale
sulla parete rettale. La paziente viene quindi posta in posizione supina, viene poi introdotto il divaricatore vaginale e la
vagina viene suturata con margini introflessi (Figura. 3).
Fig. 3 - Sutura del retto e della vagina
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Risultati
Tutte le pazienti sono state sottoposte a confezionamento di una stomia derivativa. Tutte erano in grado di deambulare
il primo giorno postoperatorio. L'alimentazione orale è stata iniziata in seconda giornata postoperatoria. Il tempo
operatorio medio è stato di 130 minuti (range, 90-150 min), e la degenza media è stata di 5 giorni (range, 3-8 giorni).
La terapia antalgica si è resa necessaria solo nel primo giorno postoperatorio. Le pazienti sono state in grado di
riprendere l’attività lavorativa dal decimo giorno post-operatorio.
La valutazione radiologica effettuata in decima giornata post-operatoria non ha evidenziato tramiti fistolosi. In due casi,
il decorso perioperatorio è stato complicato da un ematoma e da un ascesso del setto trattati con terapia antibiotica. In
due casi, si è osservato soiling notturno, e in una paziente la manometria anorettale ha mostrato una modesta ipotonia
sfinteriale. Questa sequela funzionale è stata risolta in 3 mesi mediante ginnastica sfinteriale.
La mediana di follow-up è stata di 25 mesi, con una sola recidiva (7%), che si è verificata entro 30 giorni dalla
procedura. La paziente era stata sottoposta a precedente resezione del retto per un carcinoma T3N1 basso dopo terapia
neoadiuvante. La fistola retto-vaginale recidivante è stata trattata nuovamente con TEM, e si è osservata una seconda
recidiva dopo 40 giorni. La paziente è attualmente ancora portatrice di stomia, avendo rifiutato ulteriori trattamenti
chirurgici.
Discussione
Le fistole retto vaginali costituiscono meno del 5% delle fistole anorettali (3). Lesioni da parto è la causa più comune,
verificandosi fino al 70-88% dei casi (2, 4). Altre cause includono resezione rettali anteriori (0.9-2.9%) (2), la chirurgia
vaginale, le infezioni perianali o delle ghiandole del Bartolini, proctiti attiniche e le patologie infiammatorie intestinali (3).
La fistola si può verificare anche come complicanza di una leucemia o di altre neoplasie maligne.
Molte tecniche sono state sviluppate e sperimentate nel tentativo di trattare le fistole retto vaginali. Nei primi anni 80
l’Endorectal Advancement Flap (EAF) era indicato come “gold standard” per le pazienti con fistole retto vaginali basse
mostrando inizialmente risultati molto promettenti con tassi di guarigione compresi tra il 78 e il 95%. Più recentemente
è stato riportato un tasso di guarigione significativamente più basso, soprattutto per donne che avevano subito
precedenti interventi di riparazione della fistola (5). In una review retrospettiva dalla Cleveland Foundation delle 105
pazienti, che avevano subito “EAF”, 37 presentavano fistole retto-vaginali e 21 di queste (56.8%) presentavano una
recidiva. Il tasso primario di guarigione risultava quindi del 43.2%. Gli autori concludevano sostenendo che “sebbene
l’EAF continui ad essere impiegato con successo nel trattamento delle fistole retto vaginali il nostro tasso di successi non
risulta ottimistico come quello di altri studi pubblicati e non ha mostrato un significativo miglioramento negli ultimi 5
anni” (6).
Nei primi anni 90, si è suggerito che l’interposizione di tessuto sano e ben vascolarizzato potesse essere la chiave per la
guarigione delle fistole retto vaginali. Sono state descritte multiple strategie chirurgiche per il trasferimento di tessuto
sano e non irradiato. Questi metodi includono l’uso di lembi di cute, lembi di muscolo, lembi muscolo cutanei, lembi
intestinali e il lembo Martius che include tessuto sottocutaneo e muscoli vulvari trasposti da una delle piccole labbra (7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).
E’ stato riportato l’effetto benefico dell’interposizione della fionda puborettale con un alto tasso di successo compreso tra
92 ed 100 %. Nel 2006 Oom et al (5), riportano in una serie di 26 pazienti consecutive, un tasso di guarigione del 62%
(16 pazienti). Per le pazienti che avevano subito uno o più precedenti interventi di riparazione della fistola, il tasso di
guarigione era solo del 31% in paragone con il 92% delle pazienti non sottoposte a pregressa chirurgia.
Wexner et al (21, 22) nel 2008 sperimentarono la tecnica della gracilo-plastica nell’effettuare la riparazione delle fistole
retto vaginali in un gruppo di 15 pazienti. Tale tecnica riportava un tasso di successi del 75% (range tra 60 e 100%),
determinato da fattori prognostici negativi quali la malattia infiammatoria intestinale e l’irradiazione.
Sono state utilizzate diverse altre tecniche per il trattamento delle fistole retto vaginali inclusa l’instillazione di colla di
fibrina, lembo di avanzamento di mucosa ileale con pouch o avanzamento di pouch circonferenziale, e una proctectomia
con anastomosi colo-coloanale.
Buess ha sviluppato la TEM nel 1983. In realtà questa tecnica è solitamente impiegata per il trattamento di adenomi e
cancri del retto T1 e T2.
In letteratura non è riportato alcuno studio sulla riparazione delle fistole retto vaginale con la TEM: sono stati pubblicati
solo tre case reports da Vàvra (23, 24), Darwood e Borley (25).
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Il principale vantaggio offerto dalla TEM come alternativa alla tecnica che impiega il confezionamento di un lembo è l’uso
di un approccio endoluminale che elimina la necessità di una incisione perineale, che risulta obbligata nelle altre tecniche
più invasive. Inoltre la magnificazione e la visione tridimensionale consentono un’identificazione precisa delle pareti
vaginale e rettale tramite la rimozione del tessuto sclerotico. Di conseguenza la sutura può essere eseguita su tessuto
sano che garantisce il controllo totale dell’emostasi tramite magnificazione della visione diretta. Inoltre è necessario che
ognuna di queste suture sia effettuata su piani differenti longitudinale e trasverso.
Spesso la fistola retto vaginale è associata alla stenosi del lume, soprattutto dopo chirurgia o radioterapia. Questo può
rappresentare un’oggettiva difficoltà tecnica nell’esecuzione della TEM. Nella serie presentata in questo studio in nessuna
delle pazienti, la fistola retto vaginale era associata alla stenosi del lume.
Il principale inconveniente di questa tecnica è che l’introduzione del rettoscopio non consente una dissezione distale del
retto, che deve essere eseguita manualmente, alla cieca prima dell’identificazione del piano avascolare.
L’osservazione dei criteri tecnici riportati assicura un tasso di recupero/ guarigione alto (93%), maggiore di quello
riportato da altre tecniche. Il tasso di complicanze è stato del 15%. Sono state riportate solo le complicanze minori,
prontamente risolte con antibioticoterapia.
In due casi è stato osservato soiling notturno da imputare al trauma sfinteriale causato dalla TEM e che è stato correlato
all’età delle pazienti e alla funzione sfinterica preoperatoria. Tale sequela è stata risolta entro tre mesi grazie alla
rieducazione sfinteriale. Solo in un caso abbiamo osservato una recidiva, la paziente sottoposta a secondo trattamento
TEM ha sviluppato una seconda recidiva. La paziente presentava un carcinoma rettale ed è stata inviata a
radiochemioterapia. Tale fallimento è da imputare principalmente ad un processo sclerotico dei tessuti (retto e vagina)
che non beneficiano di una rivascolarizzazione adeguata. Per ottenere risultati positivi, sembra fondamentale una lunga
curva di apprendimento per la TEM che includa una vasta esperienza nell’escissione locale di polipi. È mandatorio quindi
che un simile trattamento venga effettuato in centri altamente specializzati.
Conclusioni
In questa review viene presentata una nuova tecnica per il trattamento delle fistole retto-vaginali con la TEM. I risultati
riportati giustificano l’indicazione all’utilizzo di questa tecnica come “gold standard”, soprattutto perchè tale approccio
evita ogni incisione dell’area perineale riducendo il dolore postoperatorio e perseverando le funzioni sfinteriali.
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pelvic surgery. Obstet Gynecol 1989; 74:823.
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Autore di riferimento: Andrea Balla
Corresponding Author: Andrea Balla
Department of Surgery "Paride Stefanini", Endolaparoscopic Surgery and Advanced Technology Unit,
(Director Prof. E. Lezoche), Policlinico "Umberto I", Rome, Italy
122
L’esperienza dei medici di famiglia nell’ambulatorio Med dell’ospedale
“F.Spaziani” di Frosinone: analisi dei dati e prospettive
L’ESPERIENZA DEI MEDICI DI FAMIGLIA NELL’AMBULATORIO
MED DELL’OSPEDALE “F.SPAZIANI” DI FROSINONE: ANALISI
DEI DATI E PROSPETTIVE
THE EXPERIENCE OF FAMILY DOCTORS INVOLVED IN THE “AMBULATORIO MED”
PROJECT AT THE “F.SPAZIANI” HOSPITAL, FROSINONE: DATA ANALYSIS AND
PERSPECTIVES
Grimaldi E1, Carrano F2
1
Medico Ambulatorio Med, ASL Frosinone
2
Medico di Medicina Generale, Coordinatore Ambulatorio Med, ASL Frosinone
1
2
Doctor of Med Ambulatory, ASL Frosinone, Italy
General Practitioner, Coordinator of Med Ambulatory, ASL Frosinone, Italy
Citation: Grimaldi E, Carrano F. L’esperienza dei medici di famiglia nell’ambulatorio Med dell’ospedale “F.Spaziani” di
Frosinone: analisi dei dati e prospettive. Prevent Res 2013; 3 (2): 123-133.
Available from: http://www.preventionandresearch.com/
Parole chiave: Medicina Generale, Ambulatorio Med, Gestione codici bianchi e verdi
Key words: General Medicine, Ambulatory Med, Management white and green codes
123
Abstract
Introduzione: La Primary Health Care del Sistema Sanitario della Regione Lazio attualmente esige una riconfigurazione
organizzativa mediante una rimodulazione della rete di offerta ospedaliera ed extraospedaliera. A tal proposito, è stato
proposto dalla Regione Lazio con la collaborazione della Fimmg Lazio (Federazione Italiana Medici di Medicina Generale)
il Progetto Sperimentale Ambulatorio Med (AmbMed) “Percorso veloce codici bianchi e verdi”, che nasce dalla precedente
esperienza dell’Ambulatorio Blu (Gestione Influenza). Il 22 ed il 23 marzo 2013 si è svolto il X° Congresso Regionale
della Scuola di Formazione in Medicina di Famiglia ed il II° Congresso Regionale Fimmg Lazio in occasione del quale sono
stati presentati i dati dei risultati emersi dal Progetto AmbMed di diverse Asl ed Aziende ospedaliere del Lazio.
Obiettivi: Lo scopo di tali progetti sperimentali è che patologie di pertinenza della medicina generale possono e devono
essere risolte nell’ambito delle Cure Primarie.
Metodi: Il percorso sperimentale “AmbMed” dell’Ospedale “F.Spaziani” di Frosinone è iniziato l’11 giugno 2012 ed è
terminato il 23 aprile 2013. L’assistenza medica è stata garantita ai cittadini sette giorni su sette dalle ore 8:00 alle ore
20:00, con specifiche
modalità di accesso alla struttura di assistenza primaria situata presso il Pronto Soccorso. Le
domande di partecipazione al progetto sono state 60 ed hanno aderito al progetto 30 medici di Medicina Generale, di
Continuità Assistenziale e di Medicina dei Servizi che hanno lavorato H12 in turni di 6 ore. La modalità di accesso
all’Ambulatorio Med è stata tramite il Triage del Pronto Soccorso gestito da infermieri che indicavano il percorso più
idoneo al paziente. I pazienti con codice bianco e verde, dopo essere stati visitati dal medico dell’AmbMed, venivano
dimessi ed indirizzati al proprio medico curante oppure inviati agli ambulatori specialistici o
affidati al PS per
rivalutazione del triage. Gli ambiti di intervento degli Ambulatori Med vertevano sulle patologie trattate negli ambulatori
di Medicina generale e in Continuità Assistenziale, ricomprese nel protocollo.
Risultati: Gli accessi in AmbMed registrati sono stati 3748: codici bianchi 1124 (30%) e codici verdi 2624 (70%); il
62% di sesso maschile ed il 38% di sesso femminile. I pazienti di età inferiore ai 65 anni sono stati l’80% ed il 20%
quelli di età superiore ai 65 anni. La provenienza dei pazienti è risultata il 18% di Frosinone città ed il 75% della
provincia di Frosinone; inoltre, si è registrato il 30% di accessi di pazienti extracomunitari. Si è ottenuto un netto
superamento dei obiettivi attesi dal protocollo. I tempi di attesa alla visita dei codici bianchi e verdi si sono ridotti per
oltre il 50% (riduzione attesa del 10%) e la riduzione dei tempi di permanenza in PS dei codici bianchi e verdi è stata di
oltre il 60% (riduzione attesa del 10%). Le patologie più frequentemente diagnosticate in pazienti di età inferiore ai 65
anni sono state quelle dermatologiche-allergiche (24,6%), mentre quelle più frequenti in pazienti di età maggiore ai 65
anni sono state patologie dermatologiche-allergiche (28,42%), osteoarticolari (20,89%) ed oculari (15,75%).
Discussione e Conclusioni: Gli obiettivi definiti dal protocollo della sperimentazione sono stati perseguiti. L’analisi dei
dati, gli obiettivi raggiunti, la professionalità degli operatori sanitari e l’alto gradimento da parte dei cittadini consentono
di poter continuare il percorso innovativo con aggiornamenti sulla base dei nuovi bisogni emersi dall’attuale esperienza
integrandolo alle nuove esigenze di riorganizzazione delle cure primarie sul territorio.
Abstract
Introduction: The Primary Health Care System of Lazio Region currently requires a reconfiguration of the
organizational network of hospital and non-hospital care. In this regard, Lazio Region in collaboration with Fimmg Lazio
(Italian Federation of General Practitioners), has proposed an experimental project called “Ambulatorio Med (AmbMed):
Percorso veloce codici bianchi e Verdi”, which developed from the former project “Ambulatorio Blu” (Flu Management).
In The 10th Congress of the Regional School of Training in Family Medicine and the 2nd Regional Congress of Fimmg Lazio
124
was held on March 22-23, 2013. Here, data collected from several ASLs and hospitals involved the “AmbMed” project
were presented.
Objectives: The aim of “AmbMed” is to address and resolve illnesses of General Medicine in the context of Primary
Care.
Methods: The experimental project “AmbMed” of “F.Spaziani” Hospital in Frosinone ran from June 11, 2012 to April 23,
2013; it ensured medical care to citizens seven days a week from 8am to 8pm, extending the access to primary care at
ER. Although there were 60 requests of participation to the project, 30 doctors of General Medicine joined the project
and worked H12 in shifts of 6 hours. The access mode to the “Ambulatorio Med” was through the Emergency
Department Triage where nurses decided the appropriate priority code for the patient, according to the project protocol.
Patients with white and green codes were visited by the AmbMed doctor; then, they were discharged and addressed to
their general practitioner or hospital specialist or re-evaluated and sent back to ER for reassessment of the triage. The
areas of AmbMed intervention dealt with the pathologies treated in primary care and included in the AmbMed protocol.
Results: The Amb Med access were 3748: 1124 (30%) white codes and 2624 (70%) green codes; males was 62% and
females were 38%. The patients with < 65 years old were 80% and the ones with > 65 years old were 20%. The
patients’ origin was found of 18% by Frosinone city and 75% by Frosinone province; moreover there was 30% of access
of foreign patients. A clear overcoming of the protocol valuables was registered: the waiting times of white and green
codes was reduced more than 50% (expected reduction of 10%) and the persistence times of white and green codes at
the ER was more than 60% (expected reduction of 10%). The most frequently diseases in patients with < 65 years old
were the dermatological-allergic ones (24,6%), while the most frequently ones in patients with > 65 years old were the
dermatological-allergic (28,42%), osteoarticular (20,89%) and eyes pathologies (15,75%).
Discussion and Conclusions: The objectives defined by the trial protocol have been largely obtained. Data analysis,
achieved goals, health workers’ professionalism, high satisfaction rating from visited patients, allow us to continue in
this innovative way centred on the latest healthcare demands which resulted from this experience, integrating it on the
basis of the new requirements for the reorganization of territorial primary care.
Introduzione
Nel panorama odierno della Primary Health Care il Sistema Sanitario della Regione Lazio esige una riconfigurazione
organizzativa mediante una rimodulazione della rete di offerta ospedaliera ed extraospedaliera al fine di creare una
sempre più solida integrazione e collaborazione
tra ospedale e territorio e di potenziare l’assistenza primaria ancora
carente sul territorio rispetto alle necessità dell’attuale domanda sanitaria (1, 2).
Alla luce del complesso processo di riorganizzazione della medicina del territorio è stato proposto dalla Regione Lazio con
la collaborazione di Fimmg Lazio (Federazione Italiana Medici di Medicina Generale) il Progetto Sperimentale Ambulatorio
Med (AmbMed) “Percorso veloce codici bianchi e verdi”, che nasce dalla precedente esperienza dell’Ambulatorio Blu
(Gestione Influenza) (3, 4). Questo progetto ha consentito la gestione dei pazienti per i quali era inappropriato il ricorso
al percorso ospedaliero, privi dunque di urgenza clinica, per ricollocarli nel giusto percorso e profilo assistenziale (5). Si
è preservata l’organizzazione strutturata di uno studio di medicina generale: il medico dell’AmbMed attraverso la visita
medica aveva la possibilità di prescrivere terapie e/o accertamenti diagnostici definiti e poteva fare richiesta di
accertamenti in urgenza. In tutti i casi si consegnava al paziente una relazione clinica per il proprio medico curante.
L'attività dell'Amb Med è stata documentata attraverso il gestionale Gipse in uso presso il PS.
Il 22 ed il 23 marzo 2013 si è svolto il X Congresso Regionale della Scuola di Formazione in Medicina di Famiglia ed il II
Congresso Regionale Fimmg Lazio in occasione del quale sono stati presentati i dati dei risultati emersi dal Progetto
AmbMed di diverse Asl ed Aziende Ospedaliere del Lazio (6).
125
Obiettivi
Questi progetti sperimentali incentrati su patologie di pertinenza della Medicina generale, inappropriamente poste dai
cittadini all’attenzione dei PS, possono essere risolte nell’ambito delle Cure Primarie. Gli obiettivi prefissati sono stati:
-
la riduzione delle attese particolarmente prolungate ed una proporzionata e graduale riduzione dei tempi di attesa
per i pazienti con codici di diversa priorità;
-
una riduzione dell’occupazione di ambulatori in Pronto Soccorso per problematiche improprie;
-
maggiore appropriatezza di assegnazione del codice di priorità bianco;
-
un’adeguata informazione sugli obiettivi e sull’organizzazione del progetto sperimentale AmbMed.
Metodi
Il percorso sperimentale “AmbMed” dell’Ospedale “F.Spaziani” di Frosinone è iniziato l’11 giugno 2012 ed è terminato il
23 aprile 2013. Ha garantito l’assistenza medica dei cittadini sette giorni su sette dalle ore 8:00 alle ore 20:00,
ampliando le modalità di accesso alla struttura di assistenza primaria situata presso il Pronto Soccorso. Le domande di
partecipazione al progetto sono state 60, mentre hanno aderito al progetto 30 medici di Medicina Generale, di Continuità
Assistenziale e di Medicina dei Servizi che hanno prestato la loro attività professionale H12 in turni di 6 ore.
La modalità di accesso all’Ambulatorio Med è stata tramite il Triage del Pronto Soccorso gestito da infermieri che
assegnavano al momento dell’accettazione, in base ai protocolli vigenti, il percorso più idoneo al paziente. Per poter
accedere all’AmbMed il paziente doveva essere autosufficiente, sintomatico ma non sofferente ed avere una buona
capacità cognitiva o un adeguato supporto familiare. In accordo con il DPR 27 marzo 1992 e con le linee guida per le
emergenze ospedaliere, esistono percorsi differenziati per i pazienti che accedono in Pronto Soccorso, in base alla
priorità assegnata ai casi (Tabella 1) (3, 7). Erano previsti tre percorsi ben distinti a seconda della priorità dei casi (A, B,
C), per cui gli infermieri addetti al triage stabilivano al momento dell’accettazione il percorso più idoneo per i pazienti.
Nel percorso A venivano inclusi pazienti con codice a priorità maggiore (rosso e giallo) gestiti nell’area dedicata
all’emergenza; nel percorso B erano valutati i pazienti con codice verde che non rientravano nei criteri di ammissione
dell’AmbMed (Tabella 2); mentre, i pazienti codificati con codice bianco e verde con i criteri di ammissione suddetti
rientravano nel percorso C, per cui venivano indirizzati in AmbMed e, dopo essere stati visitati dal medico potevano
essere dimessi ed indirizzati, secondo i diversi casi, al proprio medico curante, agli ambulatori specialistici o
eventualmente rivalutati e rinviati al PS (3).
Gli ambiti di intervento degli Ambulatori Med, secondo protocollo, vertevano su tutte quelle patologie trattate negli
ambulatori di Medicina Generale e in Continuità Assistenziale per cui ci si è occupati del trattamento di disturbi muscoloscheletrici non derivanti da eventi traumatici (lombalgie e rachialgie non traumatiche, distrazioni muscolari,
sintomatologie
algiche
osteomuscolari),
disturbi
dermatologici
(punture
d’insetto
senza
reazioni
generalizzate
sistemiche, rash cutanei iatrogeni ed orticaria di modesta entità, dermatiti superficiali, prurito diffuso senza
manifestazioni cutanee generalizzzate, verruche, herpes simplex, micosi, paterecci ed unghie incarnite, cisti sebacee
flogistiche e non, alopecia, eritema solare, idrosadenite, cisti pilonidale, parassitosi cutanea, malattie esantematiche e
tumefazioni linfoghiandolari non complicate, ustioni di primo grado di estensione limitata, ferite superficiali che non
necessitano di sutura ed esiti di ferite, abrasioni, rimozione punti di sutura e medicazioni), problemi oculistici
(congiuntiviti, patologie palpebrali e degli annessi oculari, escluso corpo estraneo), otorinolaringoiatrici (otalgia,
faringodinia, riniti, faingo-tonsilliti, odontalgia, stomatiti, gengiviti, afte), urologici (infezioni vie urinarie, colica renale,
sostituzione di catetere vescicale), gastroenterologici (reflusso gastroenterico, stipsi, diarrea, dispepsia, sindrome
emorroidaria), pneumologici (sindrome influenzale, flogosi delle vie respiratorie), disturbi di ansia, attacchi di panico e
crisi ipertensive (3).
126
Tab 1 - Codici di priorità per pazienti che accedono in PS, sec. Linee guida per le emergenze ospedaliere (3)
Codice Priorità Definizione Rosso ‐ Emergenza Pericolo di vita imminente. Pz molto critico con compromissione delle funzioni vitali. Potenziale pericolo di compromissione delle funzioni vitali (coscienza, respiro, attività cardiaca). Pz mediamente critico. Non c’è pericolo per le funzioni vitali. Pz poco critico. Prestazioni sanitarie che non rivestono alcun carattere d’urgenza e che dovrebbero essere risolte dal medico di famiglia. Giallo ‐ Urgenza indifferibile Verde ‐ Urgenza differibile Bianco ‐ non urgenza Accesso alla visita Immediato % 3% 10 ‐ 15 minuti 15
% 30 ‐ 60 minuti Non stimabile 74
% 8% Tab 2 - Criteri di ammissione e criteri di esclusione dell’Amb Med
Criteri di Ammissione Codici bianchi e verdi a bassa priorità Età > 14 anni Non competenza ginecologica – ortopedica ‐chirurgica Pz autosufficiente Pz sintomatico con NRS<5 Pz con sufficiente capacità cognitiva o adeguato supporto familiare Codici bianchi non esenti soggetti a pagamento del ticket di 25,00 euro, come da disposizione di legge. Criteri di Esclusione Traumi Età < 14 anni Competenza ginecologica Patologie neurologiche acute Pz sintomatico con NRS>5 Patologie psichiatriche Deambulazione non autonoma Pz inviati in PS dal curante o da struttura sanitaria Risultati
Dati incoraggianti emersi dal report dell’AmbMed di Frosinone hanno dimostrato un netto superamento degli obiettivi
attesi dal protocollo (6,8,9). I tempi di attesa alla visita dei codici bianchi e verdi si sono ridotti di oltre il 50% (riduzione
attesa del 10%), la riduzione dei tempi di permanenza in PS dei codici bianchi e verdi è stata del 60% (riduzione attesa
del 10%) e la percentuale di accessi in AmbMed è stata crescente: nel primo trimestre Giugno-Agosto 2012 pari al 20%
degli accessi giornalieri in PS, nel secondo trimestre Settembre-Novembre 2012 è stata del 25%, nel terzo trimestre
Dicembre 2012-Febbraio 2013 pari al 35% e nell’ultimo bimestre Marzo 2013-Aprile 2013 del 30% (percentuale attesa
20%-30%) (Figura 1). Il picco di affluenza si è verificato nel fine settimana: sabato (17,7%) e domenica (12%), periodo
in cui gli ambulatori di MMG sono chiusi (Figura 2).
Gli accessi in AmbMed registrati sono stati in totale 3748 di cui codici bianchi 1124 (30%) e codici verdi 2624 (70%),
maschi 62% e femmine 38% con età inferiore ai 65 anni l’80% e superiore ai 65 anni il 20%. La provenienza dei
pazienti è risultata: 18% di Frosinone città e 75% della provincia di Frosinone (Figura 3) (6, 8, 9). Un dato rilevante
emerso è stato il 20% di accessi di pazienti extracomunitari, che hanno ammesso di recarsi in PS per l’offerta “gratuita”
127
delle prestazioni sanitarie. Questo dato è paragonabile al 15% di pazienti riscontrati in un ER degli USA, che arrivano in
PS per gli stessi motivi citati (10).
Le patologie più frequentemente diagnosticate in pazienti di età inferiore ai 65 anni sono state quelle di pertinenza
dermatologico-allergica (24,6%), mentre quelle più frequenti in pazienti di età maggiore ai 65 anni sono state patologie
dermatologiche-allergiche (28,42%), disordini osteoarticolari (20,89%) ed oculari (15,75%) (Figure 4 e 5) (6, 8, 9).
Per quanto concerne la tipologia di dimissione dei pazienti visitati in AmbMed soltanto il 2% non ha risposto a chiamata
e l’1% dei pazienti si è allontanato spontaneamente, di questi in circa la metà dei casi era stata richiesta una consulenza
specialistica. Il 95% dei pazienti, di questi il 53% codici verdi ed il 42% codici bianchi, sono stati dimessi con una terapia
a domicilio. La percentuale di assegnazione al percorso emergenza di medio-alta complessità (codici giallo e rosso) con
cambio di ambulatorio è stata dell’1% (percentuale attesa inferiore al 5%) associata ad una percentuale di ricovero
dell’1% (percentuale attesa <2%) (Tabella 3) (6, 8, 9).
Un ulteriore dato rilevante è stato lo scarso ricorso alle consulenze specialistiche ed agli esami diagnostici per codici a
bassa priorità: soltanto l’8% dei casi ha effettuato consulenza e terapia specialistica, mentre l’82% dei pazienti è stato
dimesso con una terapia a domicilio prescritta dal medico dell’Amb Med ed al 15% dei casi è stata somministrata una
terapia ambulatoriale (Figura 6). Per quanto riguarda la prescrizione di esami diagnostici, nel 5% dei casi sono stati
prescritti esami di laboratorio, il 15% dei pazienti ha eseguito in differita esami strumentali, mentre la maggior parte è
stata dimessa senza alcuna prescrizione (Figura 7) (6,8,9). Quest’ultimo dato è da mettere a confronto con i dati
riportati da uno studio effettuato dalla Scuola di Medicina Generale di una Università del Texas secondo cui nei Pronto
Soccorso degli USA c’è una sovra-prescrizione di farmaci, antibiotici in particolare, e di esami diagnostici rispettivamente
del 52% e del 25% (11).
La Regione Lazio ha stanziato per il progetto AmbMed 2.500.000,00 euro su fondi di riserva aziendali, suddivisi per 11
Ambulatori Med distribuiti sul territorio regionale, ed una centrale d’ascolto. La spesa per i 380 professionisti sanitari
coinvolti nel progetto è stata di 1.737.455 euro a cui si aggiungono i costi fissi. Il costo per singolo AmbMed è stato in
media di 164.637 euro. Valutati complessivamente le spese e considerato che gli accessi in AmbMed nella Regione Lazio
superano i 38.000, al netto si è registrato un risparmio per le casse regionali di 2.861.455 euro (12).
Tab 3 - Tipologia di dimissione dei pazienti dell’Amb Med
Tipologia di Dimissione Non risponde a chiamata Si allontana spontaneamente Ricovero Domicilio Cambio Ambulatorio www.preventionandresearch.com
% Pz
2%
1%
1%
95%
1%
128
Fig 1 - Numero di Accessi in Amb Med nei mesi di Giugno 2012 – Aprile 2013 nelle fasce orarie 8-14 e 14-20
Fig 2 - Percentuale visite in Amb Med
% VISITE
% VISITE
ORE 8
17,73
LUNEDI
13,6
MARTEDI
11,27
MERCOLEDI
13,67
VENERDI
14,47
12
0
5
10,8
ORE 10
11
ORE 11
12,3
8,7
ORE 13
17,27
DOMENICA
ORE 9
ORE 12
GIOVEDI
SABATO
13,8
6,4
ORE 14
7,7
ORE 15
7,5
ORE 16
5,6
ORE 17
6,1
ORE 18
6,4
ORE 19
10
15
20
3,3
0
129
5
10
15
Fig 3 - Caratteristiche dei pazienti visitati in Amb Med
SESSO
20%
38%
62%
7%
ETA’
MASCHI
FEMMINE
80%
RESIDENZA
PROVENIENZA
2%
PROV. FR
18%
75%
<65 aa
>65 aa
FROSINONE
ALTRI
LAZIO
13%
ALTRE
REG.
ESTERO
85%
Fig. 4 - Percentuale delle diversi tipi di patologie riscontrate in pazienti di età inferiore ai 65 anni
130
Fig 5 - Percentuale dei diversi tipi di patologie riscontrate in pazienti di età maggiore ai 65 anni
Fig 6 - Terapie mediche effettuate in Amb Med
TERAPIE ESEGUITE
TERAPIE PRESCRITTE
15%
18%
SI
85%
82%
SI
NO
TERAPIE SPECIALISTICHE
8%
SI
NO
92%
131
Fig. 7- Percentuali di richieste di esami diagnostici e di visite specialistiche in Amb Med
5%
15%
8%
72%
ESAMI DI
LABORATORIO
ESAMI STRUMENTALI
VISITE SPECIALISTICHE
NESSUNA
Discussione e Conclusioni
Gli obiettivi definiti dal protocollo della sperimentazione sono stati in gran parte perseguiti. Si è registrata la riduzione
delle attese prolungate in Pronto Soccorso di pazienti con codici di bassa priorità con conseguente proporzionata
riduzione dei tempi d’attesa per i pazienti con codice di diversa priorità, la riduzione dell’occupazione di ambulatori in PS
per problematiche improprie, un’adeguata informazione sanitaria ed una maggiore appropriatezza di assegnazione del
codice di priorità bianco per cui i pazienti non esenti hanno dovuto provvedere al pagamento del ticket di 25 euro. Tra gli
obiettivi realizzati si è verificata un’apprezzabile riduzione della conflittualità tra pazienti e personale sanitario in PS
dimostrata dall’elevato indice di gradimento e dalla percezione, da parte dei pazienti visitati, dell’innovazione del
prestazione sanitaria erogata in AmbMed.
I risultati positivi confermano la bontà dell’intuizione della progettualità Ambulatorio Med. L’aspetto economico del
progetto ha portato a livello regionale ad un risparmio di oltre 2.800.000 euro (12). Alla luce delle considerazioni emerse
dall’analisi dei dati e dal positivo rapporto costo/beneficio emerso, si auspica di poter continuare il percorso innovativo
aggiornandolo alle nuove esigenze del panorama sanitario, migliorandolo sulla base dei nuovi bisogni emersi dall’attuale
esperienza e per strutturare nuovi modelli per riorganizzare le Cure Primarie.
Ringraziamenti
Gli Autori ringraziano i medici che hanno aderito al Progetto Sperimentale AmbMed “Percorso veloce codici bianchi e
verdi” presso l’Ospedale “F. Spaziani” di Frosinone, grazie alla professionalità dei quali sono stati raggiunti gli obiettivi
prefissati.
132
Bibliografia
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nel Lazio. Mondo Sanitario rivista mensile anno XX numero 1-2 gennaio febbraio 2013. Ediz.Secup Roma.
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Guzzanti E. Lo sviluppo dell’assistenza primaria nel Ssn. In Mazzeo M.C., Milillo G, Cicchetti A, Meloncelli A. 2009:
L’assistenza primaria in Italia – dalle condotte mediche al lavoro di squadra. Ed. Iniziative sanitarie.
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Regione Lazio. Assessorato alla Salute. Progetto regionale sperimentale 2012-2013. Ambulatorio Med “Percorso
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Regione Lazio. Assessorato alla Salute. Progetto regionale sperimentale 2011-2012. Ambulatorio Blu “Gestione
veloce codici bianchi e Verdi”.
Influenza”.
5.
McCarthy M. More US patients going to emergency rooms as alterative to
primary care, report says. BMJ
2013;346:f3398.
6.
Carrano F. Relazione: “L’esperienza dell’Ambulatorio Med dell’Ospedale “F.Spaziani” di Frosinone: Analisi dei dati e
prospettive”. X° Congresso Regionale Scuola di Formazione in Medicina di Famiglia e II° Congresso Regionale
Fimmg Lazio, 22 e 23 Marzo 2013, Ferentino (FR).
7.
Santos AP, Freitas P, Martins HM. Manchester triage system version II and resource utilization in emergency
department. Emerg Med J 2013.
8.
Grimaldi E. Lazio. Pronto Soccorso. Con il medico di famiglia “in corsia” tempi di attesa ridotti del 50%”. Quotidiano
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Grimaldi E. Frosinone, con Ambulatorio Med tempi dimezzati per codici verdi e bianchi.
Sanità. 19 Apr 2013.
Bussola Sanità. 19 Apr
2013.
10. Young GP, Wagner MB, Kellermann AL, et al. Ambulatory visits to hospital emergency departments. Patterns and
reasons for use. 24 hours in the ED Study Group. JAMA. 1996 14;276(6):460-465.
11. Xu KT, Roberts D, Sulapas I, et al. Over-prescribing of antibiotics and imaging in the management of
uncomplicated URIs in emergency departments. BMC Emerg Med 2013;13:7.
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Autore di riferimento: Francesco Carrano
Medico di Medicina Generale, Coordinatore Ambulatorio Med, ASL Frosinone
[email protected]
Corresponding Author: Francesco Carrano
General Practitioner, Coordinator of Med Ambulatory, ASL Frosinone, Italy
133
Asbestos and onset of mesothelioma: Case Report
ASBESTOS AND ONSET OF MESOTHELIOMA: CASE REPORT
AMIANTO ED INSORGENZA DI MESOTELIOMA: CASE REPORT
Caciari T1, Casale T1, Sancini A1, Frati P2, De Sio S1, Sinibaldi F1, Di Pastena C1, Scala B1,
Buccisano PFM1, Capozzella A1, Di Giorgio V1, Marchione S4, Penna M4, Tomei F1, Tomei G3,
Rosati MV1
1
2
Department of Anatomy, Histology, Medical-Legal and Orthopaedics, “Sapienza” University of Rome, Italy
3
Department of Neurology and Psychiatry, "Sapienza" University of Rome, Italy
4
Department of Anatomy, Histology, Medical-Legal and Orthopaedics, “Sapienza" University of Rome, Italy
1
2
Dipartimento di Anatomia, Istologia, Medicina Legale e Ortopedia, “Sapienza” Università di Roma
3
Dipartimento di Neurologia e Psichiatria, “Sapienza” Università di Roma
4
Dipartimento di Anatomia, Istologia, Medicina Legale e Ortopedia, “Sapienza" Università di Roma
Citation: Caciari T, Casale T, Sancini A, et al. Asbestos and onset of mesothelioma: Case Report.
Key words: asbestos, mesothelioma, diagnostic criteria
Parole chiave: asbesto, mesotelioma, criteri diagnostici
134
Abstract
Asbestos is a mineral belonging to the group of fibrous silicates. Due to its remarkable resistance to high temperatures,
its conformation in fibers and its very low cost, it was used until 1991 to produce materials able of withstanding high
temperatures. The silicates of asbestos in the solid matrix were widely used in construction, in engineering, in plumbing,
in panels and sheets for ceilings, in plaster and as sound-absorbing material.
It was also widely used in the manufacturing industry for its sound-absorbing characteristics and for the production of
manufactured articles and household equipment, such as thermal insulation for high and low temperatures, flame
retardant ducts, for the production of appliances with use of high temperatures (stoves, hair dryer, etc.), in the clutches
brakes, in the baffle plate display screens in the seals, in the production of clothing protecting from heat (gloves,
fireproof suits) and in furnishing resistant to elevated temperatures.
The exposure to atmosphere containing asbestos can be the cause of several diseases such as pulmonary asbestosis,
mesothelioma and lung cancer. The amphiboles are the most dangerous forms of asbestos, and the crocidolite among
these is the one with the most neoplastic potential. However, the diagnosis of asbestos related occupational diseases is
neither simple nor automatic, a number of criteria are to be met, such as the study of immunohistochemical markers, of
biological and environmental monitoring, to assess an effective relationship. The knowledge about asbestos-related
diseases and the diagnostic criteria has evolved over time, but it is still difficult to examine patients who have
experienced clinically disease only in recent times, after 10-20 years from the last assumed exposure, due to the latency
of the disease, particularly cancer. Here are two case reports of malignant mesothelioma, of assumed asbestos-related
occupational origin: their aetiology is debated in the light of literary overview. We analyzed all scientific knowledge about
the relationship between human health and asbestos, since the beginning of its industrial use to the present day. The
leading scientific databases (Pubmed, Cochrane, Embase, Tripdatabase) were surveyed for a total of 13,551 publications,
distributed by year and topic in order to reconstruct how and when the knowledge on asbestos related diseases has
developed. The key topics surveyed were: "Asbestos and health damage ", "Asbestos and Malignant Mesothelioma".
We applied to the two cases under examination, the findings learned through our research. We found that diagnosis of
the malignant mesothelioma attributed to the two patients is not certain because the diagnostic criteria suggested by
international literature have not been strictly applied, both from the clinical point of view and from the histopathological
and immuno-chemical level.
Abstract
L'asbesto (o amianto) è un minerale appartenente al gruppo dei
dell’amianto,cioè la
silicati fibrosi. Fino al 1991,per le caratteristiche
notevole resistenza alle elevate temperature, la sua conformazione in fibre e il costo molto basso è
stato utilizzato per produrre materiali in grado di resistere alle alte temperature. I silicati di amianto a matrice solida
avevano trovato largo uso in edilizia, nell’ impiantistica resistente al calore, nelle tubature per acquedotti e fognature,
nei pannelli e fogli per controsoffittature, negli intonaci e come materiale fonoassorbente.
Anche nell’industria manifatturiera è stato largamente impiegato per le sue caratteristiche fonoassorbenti e
per la
produzione di manufatti ed oggetti di uso domestico, come isolante termico per alte e le basse temperature,condotte
antifiamma, per la produzione di elettrodomestici con utilizzo di alte temperature (stufe, phon, etc.), nei freni nelle
frizioni, negli schermi parafiamma nelle guarnizioni, nella produzione di tessuti per indumenti in grado di proteggere dal
calore (guanti, tute ignifughe) e di tessuti da arredo resistenti a temperature elevate.
L’esposizione ad atmosfere contenenti amianto può essere causa di numerose patologie come l’asbestosi polmonare, i
mesoteliomi e il carcinoma polmonare. Le forme più nocive di amianto sono gli anfiboli, fra questi la crocidolite è quella
con maggior potenziale neoplastico. Tuttavia, la diagnosi di malattia professionale correlata ad amianto non è semplice
né automatica, occorre rispettare una serie di criteri, verificando markers immunoistochimici, monitoraggi biologici ed
ambientali, anche personali, per accertare una correlazione effettiva. Inoltre, le conoscenze riguardo alle patologie
asbesto-correlate ed i criteri diagnostici si sono evoluti nel tempo, e considerando il periodo di latenza delle malattie, in
particolare delle neoplasie, è difficile verificare l’esposizione pregressa dei pazienti che hanno manifestato clinicamente
la malattia solo in tempi recenti, magari 10-20 anni dopo l’ultima supposta esposizione. Riportiamo due case report di
mesotelioma maligno, di supposta origine professionale amianto-correlata, discutendone l’eziologia alla luce di un
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excursus della letteratura. Per censire, analizzandola, tutta la conoscenza scientifica circa la relazione tra salute umana e
asbesto, prodotta dall’inizio della storia dell’utilizzo industriale ad oggi, abbiamo consultato la letteratura in rete tramite
motori di ricerca con utilizzazione di parole chiave. Sono state interrogate con questo sistema le principali banche di dati
scientifici mondiali (Pubmed, Cochrane, Embase, Tripdatabase), sono state censite un totale di 13551 pubblicazioni
distribuite per anno e per argomento che consentono di ricostruire come e in che epoca si è andata strutturando la
conoscenza sulle patologie determinate per esposizione all’asbesto. Gli argomenti fondamentali censiti sono stati:
“Amianto e danni alla salute”, “Amianto e Mesotelioma Maligno”.
In base ai risultati appresi tramite la nostra ricerca, una volta applicati ai due casi in esame, abbiamo appurato che non
vi è certezza della diagnosi di mesotelioma maligno attribuito ai due pazienti, in quanto non sono stati applicati
rigorosamente i criteri diagnostici suggeriti dalla letteratura internazionale sia sul piano clinico che su quello
istopatologico ed immuno-chimico.
Background
Asbestos is a mineral belonging to the group of fibrous silicates. Asbestos fibers can be found free or weakly bound to
each other (friable asbestos) or strongly bound to each other in the case of asbestos in compact matrix. Due to its
remarkable resistance to high temperatures, its conformation in fibers and its very low cost, it was used until 1991 to
produce materials able of withstanding high temperatures.
The silicates of asbestos in the solid matrix were widely used in construction, in resistant to heat plant engineering, in
plumbing for aqueducts and sewers, in panels and sheets for ceilings, in plaster and as sound-absorbing material.
It was also widely used in the manufacturing industry for its sound-absorbing characteristics and for the production of
manufactured articles and household equipment, such as thermal insulation for high and low temperatures, flame
retardant ducts, for the production of appliances with use of high temperatures (stoves, hair dryer, etc.), in the clutches
brakes, in the baffle plate display screens in the seals, in the production of clothing protecting from heat (gloves,
fireproof suits) and in furnishing resistant to elevated temperatures.
The exposure to atmospheres containing asbestos can be the cause of several diseases such as pulmonary asbestosis,
mesothelioma and lung cancer. The amphiboles are the most dangerous forms of asbestos and the crocidolite is the one
with the most neoplastic potential.
The inhalation of even a single asbestos fiber is able to induce the onset of malignant mesothelioma or other forms of
lung cancer. Differently from other substances and dangerous preparations, in fact, a risk threshold below which the
concentration of asbestos fibers in inspired air may be considered not harmful to health doesn’t exist. Obviously
prolonged exposure to asbestos fibers, or inhalation of large amounts, increases exponentially the chances of developing
asbestos-related malignancies. Before the eighties, the risk of exposure to asbestos was only considered work-related,
but today asbestos is estimated as environmental pollutant.
In 1992 d.l.w. 257 banned in Italy the use and the processing of asbestos and it gave the standards for decontamination
of the areas affected by asbestos pollution.
Case report
Here are the salient data taken from the documentation of two cases of pleural mesothelioma.
Case 1 was embarked for 18 years on several ships. In 2004 he underwent surgery for right pneumonectomy with
partial pericardial and right hemidiaphragm resection and subsequent reconstruction through Goretex implants, followed
by successive cycles of radiotherapy. In 2005 are discovered "anorexia, worsening dyspnea in patients operated for
mesothelioma, with laterocervical lymphadenopathy." The histopathological examination of biopsy material from
laterocervical lymph node was so reperted: "localization of malignancy with morphological features consistent with
mesothelioma".
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Subsequently a right pleural effusion was found. After thoracentesis and cytologic evaluation of pleural fluid a pleural
mesothelioma was diagnosed. The definitive histological examination gives evidence of biphasic malignant mesothelioma
infiltrating the lung, with lymph node micro metastasis pT3N1MX .
The patient's condition starts worsening, with the appearance of severe dyspnea and congestive cardio-circulatory
followed by the exitus.
From the autopsy: "The right parietal pleura is in part thickened and in part replaced by implants. absence of the right
lung is found. On the left the presence of tenacious adhesions is found. The left pleura appears thickened because of the
presence of a neoformation of lipidic consistency, that presents in section large necrotic areas; the above lesion
expatiates infiltrating diffusely chest wall, left lung, pericardium, diaphragm, up to the falciform ligament and
retroperitoneum and incorporating the mediastinal organs (esophagus and trachea).
Multiple samples of the lipidic
neoformation have been withdrawn in the pleura, the pericardium and the left lung”.
From the medical report of the histopathological examination of pleuro-pulmonary biopsy material taken during autopsy:
“Fairly cellular neoformation interesting massively visceral and parietal pleura with invasion by contiguity of the soft
tissues of the chest wall and the lung parenchyma and interesting diffusely pericardium with infiltration by contiguity of
the subepicardial myocardium and aspects of vascular invasion. The neoformation is mainly composed of atypical
elements variously twisted and arranged in corrugated, swirling structures, and included in a fibrous stroma. We
proceeded to set up preparations of neoplastic tissue treated with immunochemical techniques, in order to highlight the
possible mesothelial origin of the tumor". The following results have been achieved (Tab. 1):
Table 1 - Results of Case 1 neoplastic markers
Marker
Result
CK7
+
CK20
-
CK-AE1
+
CK-AE3
+/-
Calretinin
+
CEA
-
The data reported are not correctly interpretable as the extender did not provide the interpretation key of the symbols -,
+, + / - and, therefore, it is not possible to understand the level of cut-off applied. In fact, as we are going to describe
in detail the reactivity scales for the interpretation of the results is usually indicated.
Mr. C, a former employee of the Navy, was originally commissioned officer and, as such, embarked from 1959 to 1995.
At the age of 59 years, he was hospitalized in the emergency department for the appearance of dyspnea and pain in the
left hemithorax. He was discharged with a diagnosis of left pleurobroncopneumonia. In the discharge letter we can read:
“(…) Today we discharge (…) hospitalized in our Division from 17.03.2000 and found affected by left pleuropneumonia.
At the entrance the chest X-ray showed extensive pleuro-parenchymal thickening of the lower half of the left lung field.
By thoracentesis 1600 cc of purulent exudate liquid were extracted. On this material cytological and bacteriological
research for cancer cells was negative. Bronchoscopy was negative as regards direct or indirect signs of neoplastic
disease. (…)a detailed diagnostic investigation by thoraco-abdominal CT scan should also be carried out, since other
confounding issues can not be completely excluded”. Also, from the microbiological exam report: “Material: pleural fluid;
Microscopic examination: nothing significant. Bacterial culture (...) no growth (...)”. Subsequently, the patient was
submitted to multiple biopsies by guided video thoracoscopy in the histological report we read: “the histological and ICH
finding directs to mesothelioma, however, it has to be confirmed by appropriate clinical investigations”.
The patient was treated with chemotherapy, in the same department, he underwent a surgery left pleuropneumectomia
with resection of the diaphragm and placement of pericardial and diaphragmatic Gore-Tex patch.
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The histological report shows: “(...) Monomorphic epithelial pleural mesothelioma, multinodular, infiltrating adipose
tissue subpleural with endolymphatic invasion extended to the pericardium and the peri arteriosus tissue. Sections of
hilar bronchi without neoplastic infiltration. Reactive lymphadenitis with anthracosis without metastasis in the lymph
node taken and sent separately. Skin flap covered with orthokeratotic skin without cancer sites (...).”
Due to the onset of severe dyspnea with fever, fatigue and worsening chest pain at the site of previous surgery, the
patient was readmitted, and, after a short hospitalization for cardio-circulatory failure and supraventricular
tachyarrhythmia, he died.
In this case it is not possible to carry out a detailed analysis of the type and even of the markers used, which are,
however, mentioned in a generic manner, as "guiding" for mesothelioma and, as such, do not comply with the
international standards required under a proper medico-legal assessment.
The diagnostic quality, ie the observation of criteria useful for diagnosis
The diagnosis of mesothelioma is the result of a process today relatively standardized.
The radiological picture in the pleural localization is characterized by the lobulated profile (referable to the tumor mass
where this has reached appreciable size) which assumes the profile of the chest wall for the presence of so-called
"mamelons".
The CT is a useful aid, able to provide a better iconographic definition compared to the standard radiogram. Far from
being diriment under the point of view of the diagnosis, especially the differential diagnosis with pleural metastasis of
other cancers, it is now considered a valid means to follow the evolution of the disease and the cancer staging.
After the thoracentesis, in cases of pleural effusion it is essential to proceed as early as possible with the radiographic
examination to bring out those images, previously veiled by the effusion itself. The cytology on the fluid effusion may
provide elements for the diagnostic suspicion (and not the certainty), due to the attitude of the metastatic cells of
tumors in other locations to take a mesoteliomatosus look.
The examination of the liquid has, however, assumed a greater weight for the development of the cytochemistry and the
immunocytochemistry. Basing on the presence of specific enzymes or antigens they can allow to direct the diagnostic
suspicion towards mesothelioma or metastatic forms (1).
The diagnosis of pleural mesothelioma is based, by common consent, on the histological examination of a targeted
biopsy obtainable by pleuroscopy or surgical specimen as a result of possible thoracotomy.
The definition of the tissutal origin of the tumor in question, in particular by specific immunohistochemical markers, is
fundamental.
Nowadays, several tumor markers have been identified, which allow the differential diagnosis with other tumors, in
particular bronchial adenocarcinoma (for contiguity) and renal tumors (for distant metastases). It’s yet important to
bear in mind that not all authors agree on the validity and the preferential choice of the various markers.
The complexity of the diagnosis of malignant pleural mesothelioma (MPM) comes from the fact that, almost all the
tumors with the only exception of brain tumors, can give pleural metastases (2). It should be noted however that recent
data show that in the United States the ratio pleural metastasis / mesothelioma is 50:1.
Basing on proven scientific evidence, recent French guidelines on the MPM (3) claim that:
•
it is not recommended to base the diagnosis of MPM on clinical criteria or on chest X-ray or on analysis of pleural
•
it is recommended for the diagnosis of MPM the execution of a thoracoscopy with pleural biopsies;
•
it is always recommended to base the diagnosis of MPM on immunohistochemical
•
it is recommended to use at least two immunohistochemical markers with diagnostic value positive for MPM and
fluid;
investigation;
two markers with diagnostic value negative for MPM.
As to immunohistochemical markers, substantially the same conclusions have been reached by the most recent
literature reviews (4-5): in any case it is still worth remembering that, despite the pathologists agree that
immunohistochemistry is essential for the diagnosis of MPM, there are disputes on the specific value of certain markers
and on the choice of markers to be included in the diagnostic battery. The main difficulties persist in the differential
diagnosis between MPM and lung cancer (both adenocarcinoma and squamous cell carcinoma).
Over the past decade, we have had an increasing availability of antibodies directed against antigens
present in
mesothelioma more than in other pleural diseases (marker "positive" or "mesothelial").
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In the case of certain positive and negative marker, it is not only the frequency of expression that varies according to
the nature of the pleural pathology, but also the mode, or "pattern", with which the positive reactions are distributed
within the cell (for example cytoplasmic, nuclear or membrane pattern). In the case, then, of a third category of
markers classified by Ordoñez (6) as "miscellaneous", the pattern of positivization constitutes the essential element of
discrimination between the different pleural diseases.
It should also be remembered that the same immunohistochemical findings can be read in different ways depending on
the cut-off for positivity that has been chosen. Thus, there are authors who make a judgment of positiveness when
reactive cells account for 1% or 10%, or 30% of the total. "Scale" of reactivity for the interpretation of the results have
also been drawn up. Ordoñez, for example, distinguishes between the following degrees of positivity: ±, when there are
cells expressing the marker in percentage less than 1% of the total; +, when the percentage is comprised between 1%
and 25%; + + , between 26% and 50%; + + +, between 51% and 75%; + + + +, above 75%.
In any case, despite the high number of markers tested in the course of time, so far none of them has been identified to
have any sensitivity and absolute specificity, or nearly absolute, for mesothelioma. The immunohistochemical
recognition of this disease, therefore, is carried out with a standard of probability, evaluating the overall results obtained
with batteries, or "panel", of many markers.
The composition of the panel is determined by the differential-diagnostic needs, choosing the marker considered most
discriminating between the two compared conditions. Over the last decade combinations of positive and negative
markers have been proposed, a solution that allows to detect any suspected mesothelioma on the basis of evidence both
affirmative or negative.
The usefulness of a panel is obviously in relation with the level of sensitivity and specificity of the markers that are part
of it. In some studies, mostly dating back to the nineties, it was claimed that the panels consisting of two markers
carefully chosen are sufficient to distinguish clearly the epithelial mesothelioma from the lung adenocarcinoma, and that
their discriminatory power is not significantly increased by the addition of other elements. The most recent literature,
however, generally suggests to include in the panel no less than four markers, divided in positive and negative ones,
assuming that there is a direct relationship between the diagnostic yield of a panel and the number of its markers.
In summary, according to Ordoñez:
a. Differential diagnosis between epiteliar MPM and lung adenocarcinoma
•
Top markers positive for mesothelioma = calretinin, Keratin 5/6, podoplanin, WT1
•
Top markers positive for adenocarcinoma = MOC-31, Ber-EP4, B72.3, CEA, BG-8, TTF-1
b. Differential diagnosis between epiteliar MPM and lung squamous cell carcinoma
•
•
Top markers positive for squamous cell carcinoma = MOC-31, Ber-EP4, CEA, BG-8, p63
c. Differential diagnosis between epiteliar MPM and renal carcinoma
•
•
Top markers positive for renal carcinoma = leu-M1 (CD15), RCC Ma
According to Ordoñez (7), for the differential diagnosis between epiteliar MPM and squamous cell lung carcinoma, the
best combination is the one with two markers positive for MPM (WT1 and calretinin or citokeratin 5/6) with two negative
markers (p63 and MOC-31 ).
Still, according to Ordoñez (7), for the differential diagnosis between epiteliar MPM and lung adenocarcinoma, the best
combination is the one with two markers positive for MPM (WT1 and calretinin or citokeratin 5/6) with two negative
markers (CEA e MOC-31 o B72.3, Ber-EP4, BG-8).
In the present cases it can be argued that further laboratory analysis are absolutely necessary to document with the
necessary diagnostic certainty the mesothelial matrix of the tumors found, since, in the case of Mr. C, the use of the
markers is not defined in detail, while in the case 1, on the basis of the summary table, it appears that the positivity of
some specific markers is less than 1%.
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Latency, or the period between the first exposure and the onset of the disease
The available data on the trends of the incidence show that the risk of onset of mesothelioma increases since the
moment of the beginning of exposure, regardless of whether or not the exposure has stopped because unlike chemical
carcinogens, asbestos fibers, especially the amphiboles persist indefinitely in the tissues (8). In adequately documented
studies the average latency is between 35 and 40 years. Latency periods lower than 20 years are exceptional (9). All
tumors caused or jointly caused by known factors appear after a long latency period of years: mesothelioma, compared
with these other tumors, is characterized by the longest latency.
The latency corresponds to the duration of the pathogenic mechanism of the tumor: the process by which the inhalation
of asbestos fibers triggers the mechanism of development of mesothelioma starts immediately after the beginning of the
exposure.
The model of incidence of mesothelioma developed in epidemiology recognizes the overwhelming importance of the
latency after exposure that would dramatically affect the incidence while the dose of the exposure would have only a
linear function. This is the model of Peto (p= b * tk *, where: p is the incidence of any year; b is a constant, k an
exponent ranging between 3 and 4), reanalyzed by Boffetta Im(t)= Km x E x (t - t0)β, where:
Im(t) is the incidence of mesothelioma,
t years after the beginning of exposure;
E is the average exposure expressed in ff / cc;
Km is a constant that expresses the carcinogenic power on the pleura, which is specific to the type of industry and type
of asbestos fiber;
t0 is the minimum required latency to observe an increase of mesothelioma;
β is an exponential weighting factor related to the latency, which can also be specific for the specific cohort; the β value
is estimated about 3, the t0 value about 10 years (10) which, substantially, refer to the dose as a factor linearly
correlated to the incidence of the mesothelioma, while the latency is exponentially related.
The concept of dose should however be interpreted not so much as the effect of cumulative dose, but as a result of a
critical dose, also highly concentrated in time, able to determine the passage of a certain number of fibers to the parietal
pleura. This assumption is supported by the data of an epidemiological survey and by the subsequent follow-up related
to a cohort of textile workers, recently published (11-12), which shows that the relative risk for mesothelioma does not
change in the groups exposed for less than a year compared with those who have been exposed for twenty years or
more, while the risk increases considerably with the latency after the beginning of exposure.
The cumulative dose can be defined, ideally, through the computation of the total lung load of fiber / asbestos
corpuscles per unit of lung tissue mass, or by means of an evaluation of the level of environmental exposure, which in
turn can be measured or estimated.
In the ideal condition the objective assessment of pulmonary load produced summarizes all the aspects of qualitative
and quantitative past. In the second case the evaluation can still have its objectivity if it is the result of the summation
of situations of exposures measured over time. However, when these data are missing (in the vast majority of cases
published in the literature, especially for remote exposures), an "estimate" based on job / exposure matrices is only
applied. Sometimes it is possible a "quantitative" estimate, which tends to apply to the reality in question the objective
data available, for other working similar contexts. Other times it is only possible to carry out semi-quantitative
estimates, such as: high, medium, low exposure, which are not based on measurements. Obviously, the progressively
less reliable gradient in the definition of cumulative exposure depending on the approach used is obvious.
The above estimates may also be affected by the methodological choices of the authors. For example, in the study by
Hansen (13) on a cohort of residents in areas near the crocidolite mine of Wittenoom in Australia, the possible domestic
exposure for cohabitation with workers in the mine was not considered. The authors justify their choice with a number of
reasonings, but considering that 24 of the 27 cases of mesothelioma examined lived in the same house for workers, it is
difficult to admit that the domestic exposure did not lead a more important exposure than the environmental one, which
is instead the only one taken into account by the authors.
In Iwatsubo et al.’s research (14), a case-control, the different classes of exposure, from which the authors derive the
conclusion of a significant excess of mesothelioma for increasing levels of "cumulative exposure", are in fact
"constructed" retrospectively on the basis of matrices job / exposure without the availability of any environmental
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measure. This does not prevent authors from "proposing" "quantitative" levels of cumulative exposure, levels that
furthermore, as a precautionary measure, the authors themselves indicate in quotation marks, indicating that these
values are defined on the basis of subjective evaluations of a pool of experts, in the absence of any objective measure
levels of environmental concentrations of asbestos.
The cumulative dose, however assessed, can of course derive both from a high exposure concentrated in a narrow span
of time, or from a less important exposure prolonged in time. There is no way to distinguish in the lung tissue what
proportion is attributable to a remote exposure and what to a recent exposure, especially in the case of amphiboles.
Therefore the assessment of pulmonary loads received from the lung over time can only be the result of environmental
measures carried out during the lifetime of a professionally exposed worker.
As exemplified this condition is difficult to be found in the literary data and, in epidemiological studies, it’s applied only
in cohort studies, where data on exposure conditions during the different periods of employment of the exposed persons
are available. If such data are available, in epidemiological studies, it’s usual to proceed to the "construction" of different
"exposure categories" obtained by integrating the environmental concentrations of fibers in different periods with the
duration of exposure equal to those specific levels. For example, a cumulative exposure of 30 fibers / years could be the
result of an exposure for 1 year of 30 ff / cc, or of an exposure for 3 years at a level of 10 ks / cc, of 10 years at a level
of 3 ff / cc, or still of 30 years at a level of 1f/cc.
We still want to point out what Richard Doll and Peto Julian claimed (15) in their monography “Asbestos. Effects on
health of exposure to asbestos”. About their model on estimate of the incidence of mesothelioma in relation to the
latency they write: "The estimate of risk increases roughly in proportion to the duration of exposure up to about 10
years but much weakly subsequently and there is only a small difference among the expected effects if the exposure
stops or continues after 20 years.”
One of the major contributions to the development of knowledge of the time of latency parameter is provided by the
work of Lanphear and Buncher (16) who examined 21 case studies documenting a total of 1690 cases of mesothelioma.
99% of these had a latency period longer than 15 years, and 96% had a latency period of at least 20 years. This
observation allows to argue that the minimum latency to be considered is 20 years and that cases with latency between
15 and 20 years are outstanding.
Even the Italian Mesothelioma Registry data indicate periods of very long latency: in fact, in the recent publication of
Marinaccio et al. (17) the average latency 2544 cases registered in Italy from 1993 to 2001 was 44.6 years.
The work that follows has the essential aim of connecting the large mass of scientific information that have been
produced worldwide about asbestos and its effects on human health.
Crucial knowledge in the medical-legal has been realized internationally, because of the many causes of recognition of
damage to person.
Our work wants to provide an update on many aspects of this delicate issue.
Materials and Methods
To assess, and analyze, all scientific knowledge about the relationship between human health and asbestos, produced
since the beginning of its industrial use to the present day, we consulted the literature network by search engines with
the use of keywords.
The world leading scientific databases (Pubmed, Cochrane, Embase, Tripdatabase) were questioned and a total of
13,551 publications distributed by year and topic were surveyed, to reconstruct how and when the knowledge of the
diseases specific for asbestos exposure has developed. The key topics surveyed were: "Asbestos and damage to health",
"Asbestos and Malignant Mesothelioma ".
Here the main topics explored:
• Asbestos and its effects on human health
• Asbestos and Malignant Mesothelioma (MM)
• Diagnosis of MM
• Growth of the MM and natural history of the disease
• Medico-legal aspects
• Industrial hygiene aspects
• International Legislative aspects
• Epidemiological aspects involved in marine transportation
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Results
The number of surveyed studies is less than ten until 1964, about one hundred from 1972 to 74, about 150 until 1978.
Since 1982 there has been a growing interest with an average production per year of about 350 scientific papers. There
are two peaks, in 1982 and 2001 respectively, with 430 and 562 publications.
Through these works the human health effects following exposure to asbestos are identified and defined:
• diffuse interstitial fibrosis or parenchymal asbestosis;
• non-malignant disorders of the pleura or pleural asbestosis (thickening, plaque deposits);
• Skin lesions (warts) on hands and forearms.
Asbestosis
Parenchymal Asbestosis is a chronic progressive, irreversible pneumoconiosis, characterized by a linear diffuse
interstitial pulmonary fibrosis, resulting in prolonged inhalation of asbestos fibers. It is usually related to the duration
and the significant levels of exposure.
Asbestosis impairs organ function, is irreversible and has a tendency to evolve even after and of the exposure.
This ability of progression is likely due to the persistence of biological activity of the fibers held in the lung and of
immune phenomena.
It is a diffused lung disease that results in the formation of fibrous tissue in the areas delegated to the gas exchange
and that may reduce the oxygen from breathed air into the blood. The diagnosis is at least 10-15 years after the first
exposure, although symptoms can occur even before in case of particularly intense exposure. The earlier and the most
common symptom is the dyspnoea on exertion that increases with the worsening and broadening of parenchymal
fibrosis.
Pleural plaques
They represent a late sign of exposure to asbestos, as they appear at least 20 years after the first exposure. The plates
are small areas of fibrous thickening, often located in the lower part of the rib cage, in the posterolateral region and in
the diaphragmatic dome.
They are generally asymptomatic, they do not lead, unless they are very large, to changes in the lung function and they
may calcify.
Benign asbestos pleurisies
Pleural effusion is a benign pathological event relatively uncommon in clinical practice, although it is considered to be
the earliest pleural manifestation due to asbestos, as it can also occur after a few years after exposure.
Rounded atelectasis
The rounded atelectasis is a benign lesion, localized in sub-pleural site, with usual nodular radiological appearance. It
may be associated with exposure to asbestos as a result of recurrent benign pleural effusions, followed by an
invagination of the visceral pleura with the collapse of the surrounding tissue, or it may result from an area of visceral
pleural fibrosis exercising traction on the near lung parenchyma.
Through these works all aspects of carcinogenesis by asbestos are identified and defined.
Here a brief history of the developing of knowledges.
The number of printed research surveyed in worldwide data banks is around or below ten from 1960 to 1972 with two
exceptions: for 1966 and 1969 respectively with 18 and 27 articles.
Between 1974 and 1979 there are about 40 or so per year, while the growth of interest began in 1980 with a total of 86
studies. From 1990 to 2004 scientific interest and production will definitely raise to touch a record in the years 2004 to
2007.
The first report of international mesothelioma is by Wagner in 1960 (18), on a highly specialized Anglo-Saxon journal.
He describes 33 cases of mesothelioma in patients who had probable exposure to blue asbestos in the Griqualand West
in Asbestos Mountains.
Wagner himself (19), reported in 1993 that after the publication of his first 33 cases a dispute arose in the first place
about the diagnostic appearance and secondly about the hypothesis of an association of mesothelioma with a genetic
factor rather than with the exposure to crocidolite (actually a genetic susceptibility was subsequently detected (20)).
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Only after the first report of Wagner, of the diversity of biological effects raised at the international level as well as the
issue of the different power in the determination of mesothelioma by the different types of asbestos fibers, i.e. the
amphiboles that is crocidolite belongs to and the coil that is chrysotile. Wagner, at the time of the first report had found
cases of mesothelioma in workers from the district placed west of Kimberley, where crocidolite was mined, but not east
of Kimberley where amosite and chrysotile were extracted (21).
Hence, the authors did not have elements to believe chrysotile and amosite etiologic agents of mesothelioma.
Only later G.K. Sluis-Cremer and collaborators (22) observed, 7.8 cases in subjects exposed to amosite, with an
incidence of 44.6 cases of mesothelioma per 100,000 persons / year exposed to crocidolite, and realized concluding that
crocidolite had a toxicity for mesothelioma much higher than amosite. They also observed the relatively low risk of
mesothelioma in workers with amosite. There can be no doubt that crocidolite is far more dangerous than amosite, at
least for mesothelioma.
So at the time of the first observations - and until 1980 - crocidolite, namely the blue asbestos from South Africa, was
the kind of asbestos related to the onset of mesothelioma (23).
After the publication, in December 1965, of the acts of conference held in 1964 on “Biological effects of Asbestos”, the
International Union Against Cancer (UICC) (24), a non-governmental organization leader in the global control of cancer,
recommended to continue the investigations on the association between asbestos and cancer (25). The UICC program
itself shows that knowledge of that time required further investigation and, in any case, we were far from having
elements that could indicate rules of practical behaviour in the presence of low doses of asbestos fibers other than
crocidolite.
Not all the specialists who had dealt with these problems, using different techniques (tests on animals, inhalation,
intratracheal, subcutaneous, intraperitoneal or pleural direct administration, epidemiological investigations substantiated
or not substantiated by quantitative data on the entity of exposure) agreed on some of the data, in particular the kinds
of asbestos and the intrapulmonary deposition of the different kinds of fibers as to the size, length, diameter and shape
of the fibers themselves, as well as the assessment of the intensity of environmental exposure.
With regard to the quantitative assessment of the effects of the exposure to asbestos, more recently, in 1998, Boffetta
(10), on the basis of the known data of duration of exposure, of the type of asbestos and of the environmental
concentration assessed, as already said, the carcinogenic power of the different types of asbestos used in the different
fields of activity. Considering carcinogenic power equal to 1 for exposure to mixtures of chrysotile asbestos at 98% and
of crocidolite at 2% in the textile, he calculated a power equal to 1.5 for exposure to mixtures of chrysotile 60%,
amosite 40 % in the field of insulation, a power equal to 3.2 in the production of manufactured at amosite 100% and a
power equal to 12 in the cement industry of asbestos with a mixtures of chrysotile 89%, crocidolite10%, amosite 1%. In
these jobs environmental concentrations of airborne fibers ranged from 9 to 20 fibers / ml.
Let’s say something about the information on mesothelioma Italian occupational doctors have had.
At least until all the 80s, the possibility to have information came from journals in English, because published in United
Kingdom, Canada, Australia and South Africa, from the attendance of the annual Congress of the Italian Society of
Occupational Medicine and Industrial Hygiene and from the reading / study of specialized treatises. The magazine
“Medicina del Lavoro” in the years 1960 to 1967 only published some synthetic reviews of scientific articles issued
abroad.
Only in 1968 the first Italian scientific contribution(but in English in a time when the knowledge of the language was not
as widespread as today) was published: 6 cases of mesothelioma in the cohort of 288 patients compensated by INAIL
for asbestosis in the period 1943/1967 and died in Piedmont, Liguria and Lombardy are reported (26).
As regards, however, the appearance of contributions on mesothelioma-asbestos, it’s necessary to wait, as the first and
only contribution, the holding of a conference of specialist area, the Italian Society of Occupational Medicine and
Industrial Hygiene, held in Saint Vincent in 1971, where was the relationship of Ruby and co-workers was exposed (27).
The duration of the uncertainty regarding diagnosis and causation is clearly evident in Italy by reading only texts of
occupational medicine for the use of experts.
In fact Vigliani (28) concluded that the possibility that pleural mesothelioma, and also apparently peritoneal one, are
connected with accidental or occupational exposure to inhalation of asbestos fibers is a very interesting topic of research
for both occupational physicians and oncologists. So it is a topic of research and not an acquired certainty to be used as
a guide in daily practice. It should be noted, however, as the quoted text is, rather than a treaty, a "dispensation" for
students of medicine and, therefore, with limited diffusion.
143
The edition of 1981 of the Treaty of Sartorelli (29) and the text of Vigliani and Bonsignore of 1981 (30) report historical
updates regarding foreign literature that allow us to see how many and what are the aspects of the relationship
asbestos-mesothelioma which is object of conflicting views still far from an unequivocal recognition.
Murray in 1991 (31), recalls the difficulties encountered in the UK by the British Occupational Hygiene Society (Bohs) in
1968 suggesting the adoption of a standard of occupational exposure limit value of 2 fibers per milliliter and the
reasoning according to which it was established in 1969 a limit of 0.2 fibers / milliliter as regards the crocidolite.
Two years later, in 1993, Carnevale and Chellini (32) in the chapter on Mesothelioma wrote that the IARC evaluations
are probabilistic, qualitative and therefore of limited use in the discrimination of the carcinogenic agents for which has
not been held account the quantitative frame, implying that the IARC had not been offered an assessment for the
purposes of public health.
The many controversies about the danger of exposure to chrysotile asbestos and on the dose-effect relationship, are
again resumed in 1995 by Englund (33).
As evidence of the lack of knowledge we have the testimony of the General Directorate of Fire Prevention Services at the
Ministry of Interior, which issued a series of circulars relating to the safety standards for protection against fire that
allowed or required the use of asbestos.
We get further confirmation of regulatory delay and then of the delay of knowledge for the entrepreneurs paying
attention to the dates of publication of the Community Directives relating to restrictions on the marketing and use of
certain dangerous substances and preparations.
The 1980/1107/CEE Directive (implemented in Italy eleven years later by Legislative Decree 277/91) lists asbestos
between agents for which "when member states adopt, for the protection of workers, measures concerning an agent,
they take prevention measures provided for in Article. 4 (these are the general measures) and additional measures."
The general measures are: 1) limited use of the agent in the workplace; 2) limiting the number of workers who are or
may be exposed, and 3) technical prevention measures; 4) establishment of limit values (here we observe that the
general measures are more necessary as are exceeded the limit values that had still not been fixed at that time); 5)
protection measures involving the application of procedures and appropriate working methods; 6) collective protection
measures; 7) individual protection measures; 8) sanitation; 9) information for workers; 10) use of warning and safety
signs; 11) monitoring workers’ health; 12) keeping and updating records indicating the level of exposure; 13)
emergency measures; 14) if necessary, total or partial prohibition of the agent if the use of other means available is not
sufficient to ensure adequate protection.
The 1983/477/CEE Directive on the protection of workers from risks related to exposure to asbestos finally fixes, in the
art. 8, the limit values for occupational exposure: 1 fiber / cc for asbestos fibers other than crocidolite and 0.5 fibers / cc
for crocidolite. It’s important that in Annex II of this directive is for the first time indicated mesothelioma among
diseases that can be caused by asbestos.
In Italy, however, the entrance of mesothelioma among tabulated diseases for which there is a presumption of legal risk
(and thus a clear knowledge) happened 11 years after the above-mentioned EC directives, so only with the Presidential
Decree 336 of 13 / 4/1994 to the voice 56 of the new table Annex 4. This disease was not specifically indicated nor in
the DPR 482 of 06.20.1975 or, even less, in the Presidential Decree 1124 of 30.06.1965. In other words, until 1994 the
legislature ignored the communications of Selikoff and the Acts of the New York Academy 1964.
The Directive 1983/478/CEE forbids, for the first time, the placing on market and the use of crocidolite and provides for
the labeling of all products containing asbestos fibers. 18 years have passed since the publication of volume 132 of the
NY Academy of Sciences. The 1985/610/CEE Directive forbids the use of all asbestos fibers listed in Annex 1 regarding:
A) toys, B) materials intended to be applied by spraying; C) materials containing asbestos to be sprayed on the bottom
of the vehicle body; D) finished products in the form of powder sold to the general; E) merchandise for smokers such as
tobacco pipes and F) catalytic filters; G) paints and varnishes. These same restrictions were taken in Italy by order of
the Ministry of Health of 06.26.1986, but only the DPR 05/24/1988 n. 215 will implement the directives 1983/478/CEE
and 1985/610/CEE.
The 1987/217/CEE Directive on the prevention and reduction of environmental pollution by asbestos publics methods of
sampling and analysis hitherto not regulated.
The 1991/382/CEE Directive lowers the limit value for chrysotile to 0.6 fibers / cc and for the other asbestos fibers to
0.3 fibers / cc.
144
The 1999/77/EC Directive aims to ban the use of chrysotile asbestos fibers and art. 2 provides that Member States must
comply with the Directive by 1 January 2005.
The 83/477/EEC Directive of 19 September 1983 "on the protection of workers from the risks related to occupational
exposure to asbestos" marks a fundamental advance for knowledge and management of the asbestos problem: "Current
scientific knowledge is not such as to enable to establish a level below which there are no risks to health - one fiber per
cm3 not crocidolite and 0.5 fiber/cm3crocidolite."
In Italy since March 1993 the law 257/92 forbids:
• extraction;
• import and export;
• Marketing;
• the production of asbestos and asbestos-containing products.
The risks from asbestos in maritime professions
These risks have been analyzed much later than those of other professions; epidemiological surveys have been
conducted in various countries.

In the U.S. Jones et al. (34) analyzed the chest radiographs of 5041 naval engineers. They revealed asbestosrelated pleural abnormalities in 12% of cases. The prevalence of pleural lesions rose to 27% in those with longer
working periods.

An extensive research was conducted on 3324 seamen of the merchant marine in the United States (35). In 34.8%
of cases were observed radiologically pleural and / or pulmonary alterations due to asbestos. According to
Seidman, the prevalence was higher in the machinery sector staff (42.5%) than in the maritime of deck (36.6%),
stewards (28.4%) or staff who had worked in several sectors (30, 9%).

In Japan Kagamimori and Hosoda (36) revealed a marked difference in the prevalence of pleural plaques in the
maritime sectors. The prevalence of radiographically detectable plaques was 10% in drivers (90 examinees) and
2% in the deck crew (136 examinees).

In Greece Velonakis et al. (37) studied a series of 141 seamen in retirement. In 41% of cases were radiologically
detectable pleural and / or lung asbestos related alterations.

In Iceland, as regards incidence and mortality from cancer, a research was conducted in 1988 (38). A cohort of
477 drivers and mechanics on board was considered. The study showed a significantly increased mortality rate for
cancer of the trachea, bronchi and lungs. An investigation was also conducted in parallel to determine the smoking
habits in this occupational category, and from the survey emerged that the seamen in question did not differ from
the rest of the population, so the smoking habit could not be held responsible for the excess of cancers found.

In a study conducted in the United States causes of death in 1922 deaths of seamen of the merchant marine were
considered (39). It was observed an excess of cancers of the respiratory system.

In Italy mortality in a cohort of seafarers in Civitavecchia was examined (40).
Also the results of this study
deposed for an increase in mortality from cancer of the respiratory system. Among the tumors observed there was
also a case of pleural mesothelioma.
• Pleural mesotheliomas in maritime have been observed in different series (41) (42).
• In a series of 70 pleural mesotheliomas examined in 1982, in 5 cases the tumor could be attributed to maritime
activities (43).
Epidemiological studies on exposed workers in the international navies lie between 1982 and 2001. Before there wasn’t
adequate knowledge and awareness of the risks of mesothelioma on board ships.
Another element consistent with what has been expressed is the fact that the engineering of marine construction in
1972 was required of the use of asbestos, strictly imposed by the International Convention for the Safety of Life at Sea
and the shipping registers of the various countries, as the ship had to possess precise characteristics of isolation,
incombustibility, resistance to fire and heat, to prevent the spread of fire and damage to persons in case of fire. The
insulating materials also were necessary to cover thermal plants, engines, pipes, to avoid heat loss and to prevent
vibrations and noises.
145
Duration and natural history of the disease
The disease is very slow; according to studies on cell growth, considering the cellular doubling time of malignant
mesothelioma (275 days) and the number of doublings (30) to reach in plan a diameter of 10 mm, the median interval
estimated that runs from the first exposure to onset of the first clinical manifestation and the clinical diagnosis of cancer
is 22.6 years (44). In general, therefore, combining biological annotation with epidemiological observations on large
series we deduce that the latency period is between 20 and 40 years after exposure and cases observed between 15 and
20 years are sporadic, exceptional and are probably due to exposure previous to the first identified, misdiagnosed
because of the modest character and occurred in the general living standard.
The exposure may not be necessarily of professional kind. The unexposed population of large industrial cities or that
living in areas near to the place of production of asbestos is also exposed to the risk of mesothelioma. Wives or family
members of asbestos workers, brushing at home dusty overalls are considered at risk. More than 30% of the people
who come into contact at home with asbestos workers have radiological features of pulmonary exposure. The risk of
mesothelioma in the relatives is estimated by 1% compared with 8-13% of workers directly exposed.
In addition to those from asbestos, other exposures are held responsible for the onset of malignant pleural
mesothelioma, in particular the erionite. Other factors that may promote the onset of malignant mesothelioma are
chronic lung infections, pulmonary tuberculosis and radiation. Finally, it has been recently suspected a possible etiologic
role of the simian virus 40 (SV40). Sequences that encode for antigens of such viruses were indeed extracted from
samples of human mesothelioma and not from the adjacent normal lung tissue. Furthermore, tumors histologically
identical to human mesothelioma arise when SV40 DNA is injected into the pleural cavity of mice (44).
Discussion
The analysis of world literature clearly demonstrates that the estimates expectations for the next 20 years, given the
extent of asbestos in various fields of human activities, is rising, as are rising the claims for personal damage in the
entire world.
The international literature in this regard, poses a series of recommendations and guidelines for accurate diagnosis of
Malignant Mesothelioma liable to confusion with other diseases as cancer or not, that have nothing to do with
Mesothelioma.
The literature also indicates the dose-independence of the initiation of the process of carcinogenesis, experience having
shown that even a very small dose may represent, according to the genetic attitude or intercurrent factors, such as
SV40, necessary and sufficient cause to promote the complex process of carcinogenesis of the mesothelium. In other
words, the exposure to so-called "Trigger Dose" is an event that takes place at the beginning of the work course in all
those people who work in environments where asbestos contamination is higher than the intrinsic defense mechanisms.
The literature data on growth (doubling time of the cellular malignant mesothelioma - 275 days - and the number of
doublings - 30 - to reach a diameter of 10 mm in plan) demonstrate that the initial lesion has a very slow growth and
that requires to give pathological manifestation from functional point of view, from 20 to 40 years with a median of 22.6
years, without considering all the biological extrinsic and intrinsic variables of the organism, under the definition of
"individual susceptibility".
As previously explained, in this process there is no certainty of diagnosis of malignant mesothelioma attributed to our
two cases as diagnostic criteria suggested at international level have not been strictly applied both from the clinical point
of view and from the histopathological immuno-chemical point of view.
The modern scientific knowledge on the timing of growth of the tumor, according to the natural history of the disease,
would put the beginning of the disease in the two cases we are examining, in times very near to the beginning of the
work history and in any case in time where, of course, the knowledge on the pathogenetic MPM were non-existent (case
2), or definitely not consolidated (case 1) so as not to allow the implement or training, information, or prevention
measures of any kind. It is clear that during the early years of the working life of the two patients epidemiological
knowledge, that maturated after the 80s especially after 1988 and after 2000, were very limited. In previous years the
knowledge related were not consolidated. In fact, in international law, only Directive 83/477/EEC of 19 September 1983
"on the protection of workers from the risks related to occupational exposure to asbestos" marks an essential advance
for knowledge and management of the problem asbestos: "Current scientific knowledge are not such as to enable to
establish a level below which there are no risks to health - one fiber per cm3 not crocidolite and 0.5 fibre/cm3
crocidolite." In 1987 IARC has classified as carcinogenic to man all types of asbestos and in 1988the carcinogenicity of
146
asbestos has been reported on the texts of medicine. The abolition of the use of asbestos has been enshrined in law by
the European Union in the EU Directive 96/62. In Italy, Law 257/92 prohibits the extraction, import, export, marketing
and production of asbestos and the European legislation on face masks with high filtering power (P3) is of 1991.
We remind in the United States Jones et al. (34) In Japan Kagamimori et al. (36); in Greece Velonakis et al. (37); in the
United States (24, 39); in Iceland in 1988 (38); in Italy Rapiti et al. (40), White (41, 43).
The occasion of the first exhibition of our two cases, as it is recognized that even a very small dose may be cause a
necessary and sufficient to promote the complex process of mesothelium carcinogenesis, can probably be traced back,
in the performance of their duties, to 'inhalation of microfibers freed occasionally in the ship, and at the time of the
conjectured assumption of "trigger dose" neither case 1 or case 2 could be aware of the consequences of exposure to
asbestos fibers, nor could implement an effective prophylaxis individual with the use of effective means of protection.
The European standard that defines the different types of mask at negative pressure according to their filtering capacity
is of 1991 (EN 149). The EN 149 provides for three classes of protection: FFP1, FFP2 and FFP3 based on the efficiency of
the filter, according to European standard EN 143, 1990. The classes of protection and the filtering efficiency are
summarized in Table 2.
Table 2 - Classes of protection and filtering efficiency
Filtering facepieces
Particle filters
Minimal
FFP1
P1
78%
FFP2
P2
92%
FFP3
P3
98%
filtering
efficiency
FFP1: dust / harmful aerosol; FFP2: dust / fumes / low speed aerosols; FFP3: dust / fumes / toxic aerosol
In Italian law (DM 06/09/94 - Standards and technical methods of application of Article 6, paragraph 3, and Article-12,
paragraph 2 of the Law of 27 March 1992, No. 257, on the cessation of use of asbestos) prompted the adoption of
"mask with filter type P3 or full face masks, depending on the level of potential exposure."
Recently, it has been raised the question of the role of the microfibers in the genesis of the disease. It was therefore
developed a debate (45-47) on the possibility that pleural mesothelioma is associated in a prevalent or even exclusive
way, according to some authors, with the inhalation of asbestos fibers with special dimensional characteristics, that is to
say with a length less than 5 m and ultrafine diameter, on the order of fractions of microns. In particular, in 2005,
Suzuki in a study on samples of lung and mesothelial tissue conducted by electron high resolution microscopy reported a
percentage of the total close to 90% of asbestos fiber of length less than 5 m and diameter less than 0, 25 microns.
Given the predominance of this fraction of the total fiber found, Suzuki (48) concluded that it is not prudent to maintain
a position that assumes that the short fibers and thin to induce only a modest risk of mesothelioma.
Also in 2005, Chiappino (49) postulated an explanation of the pathogenicity of the so-called ultra-short and ultra-fine
fibers (length of few microns, diameter of the order of 0.2 m), based on two observations:
1.
Only the portion of ultrafine fibers all voted is able to overcome the barrier-lung pleura and reach the parietal
pleura (when originates mesothelioma).
2.
The distribution of the pleura is not random because these fibers are concentrated in focal points of the parietal
pleura (black spots) corresponding to the absorption of the lymphatic stomata and therefore at such points the
fiber concentration is far lower.
This hypothesis needs further evaluation, and way if confirmed, would imply some reflections on medical-legal.
In fact, assigning a predominant etiologic role in the genesis of mesothelioma for fibers ultrafine and less than 5 m in
length, it would be necessary to answer to questions concerning both the technical possibility to produce reliable
estimates of exposure (since, by definition, these fibers dimensions are not taken into account in the calculations) and
147
the technical possibility to carry out effective measures to reduce exposure by the environmental and personal
preventive devices, designed for the removal of fibers with different and "classic" size characteristics. This especially
applies to occupational exposures incurred up to the 80s.
On this subject, there was a fierce debate about the fact that the fibers USW / ultrafine detected level pleuropulmonary
are inhaled as those that is to say are fragmented in the lung when inhaled. In support of the first hypothesis (which of
course should be related to the medico-legal and hygienistic considerations above), among others, the results of
research of Gibbs and Hwang (50), Pooley and Clark (51), Wagner JC (52) and Lee and Van Orden (53) are reported.
The first show that in the work areas of the mines of crocidolite, amosite and chrysotile fibers of length less than 5
microns represent 96% for crocidolite, 88% for amosite and to 99% for chrysotile. Similar results were reported by
Pooley and Clark that, in mines of crocidolite and amosite, revealed a percentage of fibers of length less than 4 microns
equal to 85, 4% for crocidolite and to 68.2% for amosite. The data of Lee and Van Orden concern samplings in not
strictly occupational environments, that is not proper asbestos industry, such as public buildings, schools, homes, and
the data recorded refer to a percentage of fibers of length less than 5 microns equal to 90% for amphiboles and to 99%
for chrysotile.
Scientific information contained in the works of the last three years listed above (2005-2008), in fact, have a very great
value, especially to knowledge hitherto structured (basic concepts of etiology - exposure and forensic assessment). It
would be, in fact, a Copernican revolution in the appreciation of the significance of exposure, initiation and Malignant
Mesothelioma.
Conclusions

There is no certainty of the diagnosis of malignant mesothelioma attributed to our cases report as
diagnostic
criteria suggested by the literature both in terms of the clinical and histopathological and immuno-chemical have
not been rigorously applied.

On the basis of epidemiological data and cell biology of the natural history of mesothelioma, it is clear that in
these cases, where the diagnosis was confirmed by the criterion of certainty, no exposure to asbestos possibly
occurred in the 20 years that preceded the death may have played a role in the pathogenesis of the disease. In
fact, the real beginning of the same, although not clinically manifest must be dated at least 20 years before the
time of death, because, having already activated the neoplastic process, this would be indifferent to any further
exposure.

It is reasonable to place the occasion of the first exposure in working life in the first few years of activity (2/4
years), having been amply demonstrated that even a very small dose can trigger the mechanism of initiation and
progression of Malignant Pleural Mesothelioma.

It has been demonstrated by the study of literature that the formation of an accomplished knowledge of the risks
of assumption of asbestos by the respiratory route is around the 80s. In 1987 IARC has classified as carcinogenic
to humans all types of asbestos and in 1988the dissemination of knowledge on the carcinogenicity of asbestos has
been reported on the texts of medicine. The abolition of the use of asbestos has been enshrined in law by the
European Union in the EU Directive 96/62. The legislation that identifies the type of face masks according to their
filtering capacity is of 1991.

We have documented that the epidemiological studies on the risks from asbestos in the Italian and foreign navies
began in the period between the years 1982 – 2001.

At the time of the conjectured assumption of "trigger dose", therefore, none of the two cases under examination
could be aware of the consequences of exposure to asbestos fibers, nor could implement a valid individual
prophylaxis with the use of effective protective devices.

Effective personal protection equipment were not on the market until the early 90s. Only the epidemiology and
prevention technologies that were developed later in time, led to the development, patenting and production of a
mask effective to 98% in the interception and capture of asbestos fibers, the mask with P3 filter.
148
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51. Pooley FD, Clark NJ. A comparison of fibre dimensions in chrysotile, crocidolite and amosite particles from samples
of airborne dust and from post-mortem lung tissue specimens. In Wagner JC, Editor, Biological effects of mineral
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52. Wagner JC, Editor, Biological effects of mineral fibres, Lyon: IARC, 1980.
53. Lee RJ, Van Orden DR. Airborne asbestos in buildings. Reg. Toxicol Pharmacol 2008;50:218-225.
150
Corresponding Author: Francesco Tomei
Autore di riferimento: Francesco Tomei
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SUN: FRIEND OR ENEMY?
SOLE: AMICO O NEMICO?
Miraglia E1, Persechino F1, Visconti B1, Iacovino C1, Calvieri S1, Giustini S1
1
1
Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Italy
Dipartimento di Medicina Interna e Specialità Mediche, “Sapienza” Università di Roma
Citation: Miraglia E, Persechino F, Visconti B, et al. Sun: friend or enemy?
Key words: ultraviolet radiation, photoaging, photoprotection and sunscreens
Parole chiave: radiazione ultravioletta, fotoinvecchiamento, fotoprotezione e filtri solari
Abstract
Exposure to ultraviolet radiation (UVR) is the most significant environmental risk factor for all types of skin cancer.
UVR is defined as the radiation between 100 and 400 nanometers (nm) in length and are characterized further according
to wave length into ultraviolet: A (315–400nm), B (280–315 nm) and C (100–280nm). The stratospheric ozone layer
totally blocks UVC radiation and UVB wavelengths below 295nm, so 90–95% of the UVA reaches the Earth’s surface.
A wide variety of skin disease may arise in exposed areas and are at the same time induced or exacerbated by
irradiation from the sun.
Well-known acute clinical effects of UVR in the skin are inflammation (sunburn) and reactive epidermal hyperplasia
thickening of stratum corneum and tanning. Chronic changes include photoaging immunosuppression and skin cancer.
Skin cancer are mainly divided into melanoma and non-melanoma skin cancers (NMSCs), the latter including basal cell
carcinomas (BCC) and squamous cell carcinomas (SCC). Melanoma is responsible for most of the cancer related
mortalities, and NMSCs are typically described as having a more benign course with locally aggressive features.
Photoprotection is the primary strategy against photoaging, photodermatoses and photocarcinogenesis. Recommended
measures include avoiding exposure to the sun during hours of peek UV irradiation, wearing protective clothing against
ultraviolet radiation penetration and sunglasses and applying an appropriate topical sunscreens prior and during to
exposure.
Today topical sunscreens are divided into two broad categories: organic (formerly designated chemical) and inorganic
(formerly designated physical) agents. Organic sunscreens act by absorbing ultraviolet radiation that activates the
agent’s electrons from the passive to an excited state. When returning to the stable condition, energy is emitted as
warmth or fluorescent radiation. Physical agents are composed of sizable particles (titanium dioxide and zinc oxide) that
reflect and scatter ultraviolet and visible radiation from a film of inert metal particles which forms an opaque barrier. The
152
disadvantage of physical sunscreens is that lend a “bleached” to the skin, which is scarcely accepted cosmetically and
also the tan is not uniform. This is avoided by introducing nanoparticles (single particles with a diameter <100nm) that
do not make the skin white and pasty upon topical application, while maintaining the reflective effect and making them
look transparent.
These measures are necessary for prolonged outdoor activity and particularly important for individuals with light skin
phototypes, multiple or atypical nevi or a history of skin cancer. To reduce the deleterious of ultraviolet radiation to a
minimum but at the same time to obtain all the beneficial effects that sunlight provides, public education on
photoprotective measures should be promoted continually.
Abstract
L'esposizione ai raggi ultravioletti (UVR) è il principale fattore di rischio ambientale per i tumori della cute.
Gli UVR sono radiazioni con una lunghezza d’onda compresa tra i 100 e i 400 nanometri (nm) e si suddividono in
ultravioletti di tipo A (315-400nm), di tipo B (280-315 nm) e di tipo C (100-280nm).
Gli UVC e gli UVB con una lunghezze d'onda inferiore a 295nm vengono bloccati completamente a livello dello strato di
ozono mentre il 90-95% degli UVA raggiunge la superficie terrestre.
Gli UVR possono essere la causa di molte alterazioni cutanee a livello delle zone foto-esposte o aggravare patologie già
esistenti.
Tali effetti a livello della cute possono essere definiti acuti come l’eritema solare e l’abbronzatura o cronici come il
fotoinvecchiamento, l’immunosoppressione e le neoplasie cutanee.
I tumori della cute sono classificati in melanoma e tumori non-melanoma che a loro volta sono suddivisi in carcinomi
basocellulari e carcinomi spinocellulari.
Il melanoma è responsabile della maggior parte dei decessi mentre i carcinomi hanno una prognosi migliore perchè
caratterizzati da un’aggressività prevalentemente locale.
La fotoprotezione è la strategia principale contro il fotoinvecchiamento, le fotodermatosi e l’insorgenza di neoplasie
cutanee.
Le principali raccomandazioni sono evitare l'esposizione solare durante le ore più calde della giornata, indossare
indumenti protettivi e occhiali da sole e l’applicazione di filtri solari adeguati prima e durante l'esposizione.
Attualmente i filtri solari per uso topico sono divisi in due grandi categorie: biologici (precedentemente indicati come
chimici) ed inorganici (definiti precedentemente come fisici).
I filtri solari biologici agiscono assorbendo i raggi ultravioletti che attivano gli elettroni dallo stato di riposo alla fase di
eccitamento. Quando si ritorna alla condizione di stabilità, l'energia viene emessa sotto forma di calore o radiazione
fluorescente.
I filtri inorganici, composti da particelle di considerevoli dimensioni quali biossido di titanio e ossido di zinco,
costituiscono un film di particelle metalliche inerti che forma una barriera opaca a livello della cute in grado di riflettere e
disperdere le radiazioni ultraviolette e visibili. I filtri solari fisici hanno lo svantaggio di essere visibili poiché conferiscono
alla cute un colorito biancastro, non sempre accettato dal punto di vista estetico anche a causa di un’abbronzatura non
sempre uniforme. Questo fenomeno può essere evitato introducendo delle nanoparticelle (singole particelle con un
diametro inferiore a 100 nm) che rendono i filtri trasparenti e la cute non più bianca pur mantenendo l'effetto riflettente.
Queste misure protettive sono necessarie per una prolungata attività all'aperto ed in modo particolare sono importanti
per persone con fototipo chiaro, con nevi multipli o atipici o che riferiscano una storia personale e/o familiare di tumori
cutanei. Per ridurre al minimo il danno indotto dalle radiazioni ultraviolette ed ottenere tutti i vantaggi possibili
dall’esposizione ai raggi solari è opportuno educare la popolazione e promuovere continuamente le principali misure di
prevenzione ed in particolare la fotoprotezione.
Ultraviolet Radiation
Exposure to ultraviolet (UV) radiation is the most significant environmental risk factor for all types of skin cancer.
Therefore, prevention of skin cancer focuses on limiting UV exposure by sunprotective behaviors.
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The action of UV radiation on the skin follows direct absorption of energy by the molecules, in particular nucleic acids
and proteins (direct effects) and it is amplified by the presence in the context of the skin of fluorescent substances
sensitizing of endogenous (porphyrins) or exogenous (quinine, hydrocarbons) kind, responsible for the so-called
photodynamic action (indirect effects). In this case we speak of the photosensitizing substances, they absorb radiation
of a specific wavelength and remit with a length greater wave together to free radicals that are formed during the
reaction. At a molecular level the absorption of UV radiation is conditioned by the absorption spectrum of the molecules
targeted, that depends on their structural characteristics, for which it is greater the longer the wavelength of the
radiation is close to that of the absorption maximum get free the compound targeted. On the cell surface are present
photoreceptors, which transduce the signal through the activation of a transcription factor called NFkB (nuclear factor
kappa-light-chain-enhancer of activated B cells) which determines the release of various cytokines.
The prolonged exposure caused phenomena that can lead to benign keratoses in the keratinocytes and in the
melanocytes to an increased melanogenesis.
The exposure of the cells to UV rays with a wavelength between 250 and 300 nm shows as its main direct target nucleic
acids and proteins. The living organisms have a simple sensitive to UV radiation because their coatings are free of
molecules that absorb (1).
UVR is defined as the radiation between 100 and 400 nanometres (nm) in length and are characterized further according
to wave length into ultraviolet: A (315–400nm), B (280–315 nm) and C (100–280nm). The stratospheric ozone layer
totally blocks UVC radiation and UVB wavelengths below 295nm, so 90–95% of the UVA reaches the Earth’s surface.
Depending on the wavelength, UV radiation has diverse effects on the skin, and these effects can be immediate (e.g.
tanning, sunburn, indoor tanning) or long-term (e.g. photoaging, immunosuppression, photocarcinogenicity).
The radiation is absorbed by the melanin that exerts a protective action, as demonstrated by the fact that if the color of
the skin is more clear, the sunlight sensitivity is increased.
UVA are divided in short wave UVA (320–340nm) and long-wave UVA (340–400nm), which is the most of UVA radiation.
While the exposure to UVA usually remains constant, the UVB exposure occurs more in the summer. Effects of UVA
manifest usually after a long duration of exposure, even if doses are low. UVA activate enzymes called metalloproteases,
which have the function of degrading elastin and collagene, caused the reduction in skin elasticity and increased
wrinkling.
UVA radiation reach the layers of skin and produce reactive oxygen resulting in acute and chronic changes. UVA
radiation can cause nuclear and mitochondrial DNA damage, gene mutations and skin cancer, dysregulation of
enzymatic chainreactions, immunosuppression, lipid peroxidation (membrane damage), and photoallergic and phototoxic
effects. Furthermore ultraviolet A (UV-A) are responsible for skin aging. Now use of UV-A emitting lamps in sunbeds for
recreational tanning has raised concern about artificial sources of human exposure (2).
Ultraviolet B (UV-B) can also cause erythema (sunburn),changes of pigmentation, skin cancer, and immunosuppression.
Both UVA and UVB radiation can cause sunburn, photoaging reactions, erythema, and inflammation. However, solar UVB is crucial in the synthesis of vitamin D, because it induces the transformation of ergosterol in the skin vitamin D,
necessary because the deposition of calcium in the bones occurs normally. Few studies suggest that vitamin D could
reduce the risk of breast, prostate and colorectal cancer (2).
Ultraviolet C (UV-C) is virtually completely screened out by the Earth’s atmosphere, and is thus a negligible source of
adverse human health effects.
Immunosuppression
Sun exposure itself can also cause both local and systemic immunosuppression depending on the area of exposure and
the dosage of UV radiation. Systemic immunosuppression, such as in organ transplantation patients, can lead to an
increased risk of skin cancer, as evidenced by the frequent development of non-melanoma skin cancers in patients who
have undergone organ transplantation, with reported incidence rates of 21% to 50% (3, 4).
The immunosuppressive and carcinogenic effects of UV light on the skin are complex, involving a variety of cell types,
including antigen-presenting cells, lymphocytes, and cytokines. UV radiation can cause dysregulation of antigenpresenting cells such as Langerhans cells and dermal dendritic cells, which in turn can activate regulatory T cells to
suppress the immune system.
UV radiation can also induce keratinocytes to produce immunosuppressive cytokines that inhibit the production of a
number of “repair cytokines” that fix UV-induced DNA damage. The repair cytokines can mitigate UV-induced
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immunosuppression (3, 5). Both UV-A and UV-B interact to enhance UV-induced immunosuppression, and this can occur
even at doses that do not cause erythema (6).
Skin Disorders
A wide variety of dermatoses may arise in exposed areas and are at the same time induced or exacerbated by
irradiation from the sun.
Well-known acute clinical effects of UVR in the skin are inflammation (sunburn) and reactive epidermal hyperplasia
thickening of stratum corneum and tanning. Chronic changes include photoaging immunosuppression and skin cancer.
The skin has some repair capacity of UVR-induced damage, provided that UVR exposure is avoided. According to some
authors the acute effects are reversible, whereas the chronic degenerative changes tend to accumulate in the tissue
over time.
Tanning
The UV exposure in few seconds can lead to the formation of reactive oxygen species, which have the rule to photooxidation of preexisting melanin result in immediate pigment darkening which resolves in just a few hours, whereas
more persistent pigment darkening occurs 2–24 h after UV exposure after redistribution of the photooxidized preexisting melanin. The photoprotection gained from the adaptive formation of new melanin in response to UVB takes
place until 3 day after UV exposure.
Sunburn
Excessive exposure to UV radiation leads to sunburn, this effect is mainly due to UVB. Sunburn are the most common
damage to the skin and cause redness and intense burning sensation and sometimes pain, 4-6 h after exposure to the
sun. Intense exposure to UV light, intermittent during childhood and adolescence leads to the formation of blisters and
burns, increasing the risk for basal cell carcinoma, malignant melanoma, actinic keratosis and squamous cell carcinoma.
Indoor Tanning
In Europe, the sunbed fashion follows a strong South-to-North gradient. The sunbed fashion started in the 1980s in the
Nordic countries and extended in more Southern countries in the 1990s. Surveys in Europe and North America indicate
that between 15% and 35% of women, and between 5% and 10% of men 15–30 years old have used sunbeds (7, 8). In
Sweden, after 1995, 70% of females and 50% of males 18–50 years old reported sunbed use (9, 10). In the late 1990s,
the indoor tanning fashion rapidly extended to Mediterranean areas like the north of Italy (11, 12).
The National Institute of Environmental Health Sciences (NIEHS) warns that solar UVR and exposure to sunlamps and
tanning beds are carcinogenic. It has been suggested that artificial UVR is linked to melanoma development (13). The
effects of natural and artificial UV exposure may take 20 or more years to produce skin cancer. In a study, it was
estimated that people using artificial UV tanning have a 2–3 fold increased risk of NMSCs (14). A recent study showed
that tanning-bed bulbs emit mostly UVA radiation and 5% UVB. In general, young women were more frequent users of
tanning beds than men. In addition, there is a positive correlation between tanning bed usage and melanoma.
Actinic Elastosis and Cutis Rhomboidalis Nuchae
Any sunlight-exposed skin show elastosis histologically. Often there are no distinct clues, but in other cases there may
be a yellow tint. Perioral and periorbital wrinkles are early accompanying signs.
The clinical picture of deep furrows in rhomboid pattern on the nape associated with thickened skin and yellow plaques
is known also as farmer's neck or sailor's neck (Fig.1). It is less common in women, because of the usual protection of
the nape by the hair.
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Fig.1 - Cutis rhomboidalis nuchae with nodular basal cell carcinoma.
Photoaging
Aging is a continuous phenomenon, much less striking in its appearance than photoaging (Fig.2).
Photoaging is a long-term effect of UV exposure and refers to the cumulative, degenerative process of external or
premature aging of the skin caused primarily by UVA radiation.
Aged skin shows a slight atrophy of the epidermis, Langerhans cells tend to decrease while the dryness of the skin tends
to increase, resulting in a state of skin xerosis. In the dermis in aging skin the elastic fibers tend to decrease, the
capillaries become fragile, collagen metabolism is slower, and there is a progressive lowering in concentration of
glycosaminoglycans. Radiations produce the formation of pirimydine dimers. UVB affects mainly cells down to the
epidermal basal cell layer, whereas UVA penetrates into the dermis. The aging alters gene expression of keratinocytes,
while the photoaging increases inducibility of photooncogenes by ultraviolet light. Damage induced directly by radiation
or else by means of free radicals liberates cytokine (15).
Fig. 2 – Fotoaging
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Actinic Keratoses (AK)
Actinic keratoses or solar keratoses are intraepithelial skin neoplasms constituted by atypical proliferation of
keratinocytes. AKs were previously considered precancerous or premalignant lesions with a potential for evolving into
SCCs. In recent years, they have been redefined as malignant neoplasms, since they are squamous cell carcinomas in
situ, and thus precursors of invasive squamous cell carcinoma.
They are located on sun-exposed sites, typically the dorsal areas of the hands, the forearms, the face and the scalp.
They may be associated with other stigmata of sun-damaged skin, such as telangiectasia, irregular pigmentation, solar
elastosis or skin atrophy. There are several clinical subtypes of actinic keratoses, including the erythematous and the
hypertrophic one.
The cutaneous horn or cornu cutaneum is considered by some a
type of hypertrophic AK.
They are often
asymptomatic, but common signs and symptoms include pruritus, burning or stinging pain, bleeding and crusting (16).
Their presence indicates longterm sun damage and identifies a group of individuals at high risk for developing SCC, BCC
and to a lesser extent melanoma (17). Several studies have shown that pain and inflammation are signs of AK
progression to SCC. The risk of progression is difficult to assess and varies in the literature from less than 1 to 20%
(18). The inability to predict which AKs will persist, regress or proceed to SCCs makes treatment of all AKs
indispensable.
Treatment aims to clinically evident lesions but also non-apparent lesions in the cancerization field.
Tumour
Solar radiation is the main risk factor for the major forms of skin cancer. They are mainly divided into melanoma and
nonmelanoma skin cancers (NMSCs), the latter including basal and squamous cell carcinomas (BCC and SCC,
respectively). Melanoma is responsible for most of the cancer related mortalities, and NMSCs are typically described as
having a more benign course with locally aggressive features. Nevertheless, they represent “the most common type” of
cancer in humans and they can result in significant disfigurement, leading to adverse physical and psychological
consequences for the affected patients. Basal cell carcinoma occurs about four times more frequently than SCC (19, 20).
BCC
Basal cell carcinoma is the most common malignant neoplasm in humans; it accounts for 75% of cases of NMSC,
whereas squamous cell carcinoma accounts for the remaining majority of NMSC cases. BCC is extremely locally invasive
and destructive but only rarely metastases (21).
Different types of BCC can be distinguished clinically: nodular (Fig.1), cystic, pigmented, superficial, morphea-like and
ulcerative. The nodular and cystic variants are usually found on the face, and are up to 10 mm or more in diameter
(22).
The morphoeic type shows scarring and a diffuse edge and is also often found on the face, whereas multicentric
superficial tumours, which can extend to several centimetres in diameter, typically occur on the trunk.
Diagnosis is primarily clinical and is completed with histological confirmation. Punch biopsy is the preferred biopsy
method; sometimes a shave biopsy is, however, also adequate.
Dermoscopy is used as an aid for diagnosis of BCC, with maple leaf-like structures, blue-ovoid nests, blue-gray globules,
spoke-wheel structures, and arborizing blood vessels seen upon examination (23).
Squamous Cell Carcinoma
(SCC)
Squamous cell carcinoma has a destructive pattern of growth and it metastasizes. While sporadic BCC develops de novo,
SCC arises from precursor lesions of actinic keratosis and Bowen’s disease, and represents a multistep accumulation of
genetic damage. Like BCC, it is more commonly found in men than in women.
Sex-related differences in exposure to the sun during occupational and leisure activities, in the use of sun protection,
and scalp hair are probably reasons for the higher prevalence of NMSC in men (19). Typically, SCC is found in sunexposed skin such as the head, neck, and back of the hands of elderly individuals. SCC tends to present as a rapidly
growing pink or red nodule or plaque, which may be hyperkeratotic or ulcerated. It may also be pigmented, verrucous or
appear as a thick cutaneous horn. Progressive tumor invasion results in tenderness and fixation to underlying tissues.
Especially in the head and neck region, an enlarged lymph node may indicate tumor metastasis.
Any persistent, enlarging, or non-healing lesion, particularly on a sun-exposed site, must be evaluated histologically.
157
At an early stage, it is easily cured, usually by surgical removal, but if untreated it may cause local destruction of
underlying structures or spread to regional lymph nodes (23).
Lentigo Maligna and Lentigo Maligna Melanoma
Lentigo maligna (LM) is a subtype of melanoma in situ with a prolonged radial growth phase.
If left untreated, LM may evolve into the invasive form of lentigo maligna melanoma (LMM).
LMM is the most common subtype of melanoma on the face; its presentation may be quite subtle, particularly in early
stages and delayed diagnosis is common (24).
The most common location is on the chronically sun-exposed face, most commonly cheeks and nose, then neck, scalp
and ears.
LM pathogenesis is thought to be associated with cumulative, and not intermittent, sun exposure (25). It presents as a
flat, slowly enlarging macular lesion with poorly defined irregular borders, asymmetry and pigment variation, persisting
for years on chronically sun-exposed skin of elderly individuals.
LMM is frequently larger than LM and may continue to be macular, although a nodular portion is often seen within the
macule as the lesion progresses (Fig.3).
Fig. 3 - Lentigo maligna melanoma of the cheek
Early clinical detection of LM is imperative, though often very difficult. Differential diagnoses include solar lentigo, early
lesions of seborrheic keratosis, lentigo maligna melanoma, lichen planus-like keratosis, pigmented actinic keratosis and
melanocytic naevus (26).
Melanoma
While the relationship between UV exposure and basal cell and squamous cell carcinoma is very clear and well
documented, the role of UVR in the induction and progression of melanoma remains unclear. The likelihood of an
individual developing melanoma is the result of a combination of inherited or predisposition and exposure to
environmental factors relevant to tumorigenesis.
It is a malignant skin tumour and appears as pigmented atypical lesion or with nodular (Fig.4) or ulcerated aspect.
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Fig. 4 - Nodular melanoma of the arm
Melanocytic lesions do not necessarily appear on the most heavily sun-exposed parts of the body, nor do they correlate
with occupational or cumulative exposure to sunlight. Regardless, it is believed that the major risk for melanoma is skin
color and skin reaction to sunlight. It has been shown that fair-skinned people who burn only and never tan after
sunlight exposure have a relatively higher incidence of melanoma as pigmentation is inversely correlated with the
incidence of cutaneous melanoma (27). A history of childhood sunburn may be sufficient to result in the formation of
melanoma in later years (28), while some studies suggest that recreational activity resulting in adult sunburn is
associated with melanoma risk (29).
Photoprotection
Photoprotection is the primary strategy against photoaging, photocarcinogenesis and photodermatoses. Recommended
measures include avoiding exposure to the sun during hours of peek UV irradiation, wearing protective clothing against
ultraviolet radiation penetration and sunglasses and applying an appropriate topical sunscreens prior and during to
exposure (30). These measures are necessary for prolonged outdoor activity and particularly important for individuals
with light skin phototypes, multiple or atypical nevi or a history of skin cancer. In fact UV radiation has been included in
the Tenth Report on Carcinogenesis published by the National Institute of Environmental Health Sciences.
Sun light is vital for us, conferring important health benefits, many of which are mediated by the synthesis of vitamin D
however in a skin cancer prevention strategy, behavioral measures (wearing protective clothes and reducing sun
exposure to a minimum) play a key role (31).
The best technique for reducing ultraviolet exposure is to avoid the sun in the middle of the day, because at the solar
zenith the sun’s rays pass though less of the atmosphere that absorbs less ultraviolet radiation (32).
There is evidence that topical sunscreens are able to prevent UV –induced skin damage, reduce the incidence of some
skin cancers such as squamous cell carcinoma and attenuate new nevus development (33, 34). Obviously these
products must be safe and stable not only for humans but also for the environment. The protective effects of novel
sunscreens include direct absorption of photons from both UVA and UVB, inhibition of chronic inflammation, modulation
of immunosuppression, induction of apoptosis and antioxidant activity (35).
Today topical sunscreens are divided into two broad categories: organic (formerly designated chemical) and inorganic
(formerly designated physical) agents. Organic sunscreens act by absorbing ultraviolet radiation that activates the
agent’s electrons from the passive to an excited state. When returning to the stable condition, energy is emitted as
warmth or fluorescent radiation. The most recently introduced chemical agents have been MEROXYL and TINOSORB
filters present in our sunscreens for some years. Terephthalydene dicamphor sulfonic and drometrizole trisiloxane
(Meroxyl SX and XL) absorb UVB and UVA radiation, Tinosorb M and S both absorb and reflect photons (35,36
Physical agents are composed of sizable particles (titanium dioxide and zinc oxide) that reflect and scatter ultraviolet
and visible radiation from a film of inert metal particles which forms an opaque barrier. The disadvantage of physical
sunscreens is that lend a “bleached” to the skin, which is scarcely accepted cosmetically and also the tan is not uniform.
159
This is avoided by introducing nanoparticles (single particles with a diameter <100nm) that do not make the skin white
and pasty upon topical application, while maintaining the reflective effect and making them look transparent (35).
The sun protector factor (SPF) is a widely accepted method of measuring sunscreen efficacy and is defined as the sun
radiation dose (mainly UVB) required to induce the minimum erythematous dose (MED; the threshold dose that can
produce sunburn ) after application of 2 mg/ cm2 of sunscreen divided by the dose producing 1 MED on unprotected
skin. An SPF of 2 absorbs 50% of UVB, SPF of 8 can filter out 87.5%, SPF16 93.6%, SPF 32 96.9% and SPF 64 98.4%
(30).
The most important factors for effectiveness of the sunscreens are the application of a liberal quantity of sunscreen,
followed by the uniformity of application, the SPF and the specific absorption spectrum of the agent used. Application of
sunscreens to exposed sites should be done 15–30 minutes before going out into the sun and repeated after swimming
followed by toweling, friction with clothing or sand, and sweating. In these cases water resistant or waterproof
sunscreens are preferred. Broad-spectrum sunscreens with adequate UVA protection should be used and sunscreens
should not be abused in an attempt to increase time in the sun to a maximum.
To reduce the deleterious of ultraviolet radiation to a minimun but at the same time to obtain all the beneficial effects
that sunlight provides, public education on photoprotective measures should be promoted continually.
160
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Corresponding Author: Emanuele Miraglia
Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Italy
Autore di riferimento: Emanuele Miraglia
Dipartimento di Medicina Interna e Specialità Mediche, “Sapienza” Università di Roma
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volume 3 number 02 - Prevention and Research

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