vol. cxxii no. 2/2019 august military medicine · cristian v. toma, cristian s. sima, daniel g....

• Academician General Victor Voicu at the anniversary

• Effect of the selective serotonin re-uptake inhibitors over coagulation in patients with depressive disorders – a systematic review and

retrospective analysis

• Improved methodology of using simulators develops better practical skills in laparoscopy of future residents

• Current review of surgical management options for rotational alignment of the femoral and tibial component in total knee replacement

• The risk of bioterrorist and biocrime attack in the contemporary world

• The concept of biological warfare and real biological attacks

• Morphological characteristics of the celiac-mesenteric trunk

• Local treatment options for management of loco-regional esophageal squamous cell carcinoma

• Methods of assessing stable coronary artery disease by non-invasive imaging techniques

• Endoscopic eradication of nodular gastric vascular antral ectasia by using band ligation after argon plasma coagulation

• Death due to a rare posttraumatic complication: fat embolism

• Papillary thyroid carcinoma arising on a hypertrofic pyramidal lobe

• Atypical Cogan syndrome; case report

• Patient-physician communication, an essential condition for an effective medical act

• The tree we generally throw stones at

www.revistamedicinamilitara.ro

Founded 1897 • New Series

Vol. CXXII • No. 2/2019 • August

REVISTA DE MEDICINĂ MILITARĂ

Military Medicine

Romanian Journal of

Journal included in Web of Science, Emerging Sources Citation Index, Index Copernicus International, National Library of Medicine Catalog, Ulrich’s Periodicals Directory database, Directory of Open Access Journals, Directory of Research Journals Index, Eurasian Scientific Journal Index, Science Library Index and Open Academic Journals Index.

Editorial Board of Romanian Journal of Military Medicine

Under the patronage Romanian Association of Military Physicians and Pharmacists Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Honorary Editor Acad. Victor Voicu MD, PhD

Editors-in-Chief Florentina Ioniță Radu MD, PhD, MBA Dan Mischianu MD, PhD

Executive Editors Daniel O. Costache MD, PhD, MBA Victor L. Purcărea PhD, MBA

Associate Editor Mariana Jinga MD, PhD, MBA

Redactors Raluca S. Costache MD, PhD, MBA – Bucharest Mihail S. Tudosie MD, PhD – Bucharest

Editorial Assistants Ioana Bratu MD Cristina Solea

Technical Secretary Oana Ciobanu Ionuț M. Olteanu

Publisher Carol Davila University of Medicine and Pharmacy Publishing House

International Editorial Board

Natan Børnstein (Israel) Silviu Brill (Israel)

Cris S. Constantinescu (UK) Daniel Dănilă (USA)

Stergios Ganatsios (Greece)

Mihai Moldovan (Denmark) Ioan Opriș (USA)

Gerard Roul (France) Erwin Santo (Israel)

Adrian Săftoiu (Denmark) Ioanel Sinescu (Romania)

C. Ionescu Târgovişte (Romania) Radu Ţuţuian (Switzerland) Shyam Varadarajulu (USA) Peter Vilmann (Denmark)

Victor Voicu (Romania)

Scientific Publishing Committee

Adrian Barbilian (Bucharest) Anda Băicuş (Bucharest)

Cristian Băicuş (Bucharest) Andra R. Bălănescu (Bucharest)

Mircea Beuran (Bucharest) Ovidiu Bratu (Bucharest)

Daciana Brănișteanu (Iași) Dragoș Bumbăcea (Bucharest)

Marian Burcea (Bucharest) Sofia Colesca (Bucharest)

Gabriel Constantinescu (Bucharest) Silviu Constantinoiu (Bucharest)

Dan Corneci (Bucharest)

Raluca S. Costache (Bucharest) Dragoș Cuzino (Bucharest)

Camelia Diaconu (Bucharest) Mircea Diculescu (Bucharest)

Lidia Dobrescu (Bucharest) Cosmin Dobrin (Bucharest)

Dumitru Constantin Dulcan (Bucharest) Silviu Dumitrescu (Bucharest)

Carmen G. Fierbințeanu (Bucharest) Cristian Gheorghe (Bucharest) Liana S. Gheorghe (Bucharest)

Viorel Jinga (Bucharest) Carmen Moldovan (Bucharest)

Ovidiu Nicodin (Bucharest) Tudor Nicolaie (Bucharest)

Ana Maria Oproiu (Bucharest) Carmen Orban (Bucharest)

Bogdan A. Popescu (Bucharest) Dragoș Popescu (Bucharest)

Aurelian E. Ranetti (Bucharest) Mugurel Rusu (Bucharest)

Carmen A. Sîrbu (Bucharest) Silviu Stanciu (Bucharest)

Ion Țintoiu (Bucharest) Daniel Vasile (Bucharest)

Dragoş Vinereanu (Bucharest)

REDACTION

B-dul Eroii sanitari, Nr.8, Sector 5, București, Tel/fax 021/318.07.59, tel. 021/318.08.62/Int. 199; Email [email protected]

Romanian Journal of Military Medicine (RJMM) is included in Romanian College of Physicians Medical Publications Index.

www.revistamedicinamilitara.ro

Romanian Journal of Military Medicine, New Series, vol. CXXII, No 2/2019, August

ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126

1

Founded 1897 • New Series

Vol. CXXII • No. 2/2019 • August

Edited by the Romanian Association of Military Physicians and Pharmacists.

Contents

EDITORIAL

*** ● Academician General Victor Voicu at the anniversary 5

SYSTEMATIC REVIEW

Octavian Vasiliu ● Effect of the selective serotonin reuptake inhibitors over coagulation in patients with depressive disorders – a systematic review and retrospective analysis 7

REVIEW ARTICLE

Cristian V. Toma, Cristian S. Sima, Daniel G. Radavoi, Traian Constantin, Daniel L. Bădescu, Viorel Jinga ● Improved methodology of using simulators develops better practical skills in laparoscopy of future residents 12

Bogdan Crețu, Cătălin Cîrstoiu, Ștefan Cristea ● Current review of surgical management options for rotational alignment of the femoral and tibial component in total knee replacement 16

ORIGINAL ARTICLES

Ioana A. Gal, Teodora B. Eremia, Mihail S. Tudosie, Viorel Ordeanu ● The risk of bioterrorist and biocrime attack in the contemporary world 21

Teodora B. Eremia, Ioana A. Gal, Iulia M. Staicu, Mihail S. Tudosie, Viorel Ordeanu ● The concept of biological warfare and real biological attacks 26

P. Bordei, R. Baz, V. Rusali, Cristian R. Jecan, V. Ardeleanu ● Morphological characteristics of the celiac-mesenteric trunk 31

Tülay Eren ● Local treatment options for management of loco-regional esophageal squamous cell carcinoma 36

Carmen M. Voicu, Tiberiu Nanea ● Methods of assessing stable coronary artery disease by non-invasive imaging techniques 43

CLINICAL PRACTICE

Săndica Bucurică, Mihaela Ailenei, Mariana Jinga, Florentina Ioniță Radu ● Endoscopic eradication of nodular gastric vascular antral ectasia by using band ligation after argon plasma coagulation 51

RJMM Romanian Journal of Military Medicine

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Cristina Podilă, Mihaela C. Șomlea, Bogdan A. Buhaș, Adrian S. Judea, Andreea A. Hleșcu, Nicolae Nicoară, Flavia Săndoiu, Paula Marian, Bianca Hanganu, Irina S. Manoilescu ● Death due to a rare posttraumatic complication: fat embolism 56

Rodica Petriș, Ionuț B. Sandu, Adina Dragomir, Dumitru Ioachim, Cristina Iosif, Ruxandra Dănciulescu-Miulescu, Alexandra Mirică, Diana Păun ● Papillary thyroid carcinoma arising on a hypertrofic pyramidal lobe 62

Gabriela C. Mușat, Roxana E. Decusară, Ovidiu Mușat ● Atypical Cogan syndrome; case report 66

VARIA

Carmen M. Voicu, Consuela M. Gheorghe ● Patient-physician communication, an essential condition for an effective medical act 73

Mihail Mihailide ● The tree we generally throw stones at 77

Guidelines for authors 85

Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine

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5

EDITORIAL

Academician General Victor Voicu at the anniversary

An anniversary is rather meant to reflect on the past, present

and future, being at the same time, and a reason for

celebration.

On Wednesday, June 26, 2019, the book of Academician

Victor Voicu – "Under the sign of Hippocrates" was released

in the Auditorium of the Romanian Academy – a book

recently published by the prestigious European Idea

Publishing House. It was a moment of great and wonderful

celebration.

We will only remind you the essential things about

Academician General Victor Voicu – a distinguished and

emblematic personality of civil and military medicine (in the

context in which the assertion of civilian physician – military

physician is increasingly obsolete) from our country.

Born June 29, 1939 in the village of Bolovani, Dambovita

county, student of "St. Sava" National College in Bucharest,

transferred in the last year to "Ştefan cel Mare" Military

Highschool in Iaşi (currently in Câmpulung Moldovenesc) –

the moment when he put on the military coat, selected from

the best for the Medical-Military Institute, the Faculty of

Medicine – Medical Pharmace-utical Institute in Bucharest,

which he graduated in 1962, apparently we would not have

too much to say... and yet!

He chooses pharmacology and clinical pharmacology and the

intuition of his master, Alfred Teitel, imposes the future cre-

ator of the School of Pharma-cology, Toxicology and Psycho-

pharmacology from our country.

University Assistant, starting from 1966 Scientific Researcher

at the Radiobiology and Molecular Biology Center, since

1972 Associate Professor and Head of the Pharmacology

Department of the recently established Faculty of Medicine

from Craiova, since 1990 Professor of Pharmacology,

Toxicology and Psychopharmacology at the University of

Medicine and Pharmacy "Carol Davila", Head of the Medical

Department of the Ministry of National Defense between

1990-1995, Commander of the Medical-Military Scientific

Research Center for 26 years (1987-2013), Corresponding

Member (1991) and Full member (2001) of the Romanian

Academy, Secretary-General in two legislatures and Vice-

President of this High Authority from April 2018.

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The life, work, efforts and achievements of a MAN cannot be

reduced only to the previous sentence. Those who want to

learn more about the frankness and the visionary spirit of

Academician Victor Voicu, can do that by making use of

"search engines", as they say nowadays.

Academician Nicolae Breban enlightened the thoughts of the

audience when he pronounced the word "energetic", adding

it to the joy felt by those present at the release of the book I

previously mentioned.

General Academician Victor Voicu, a descendent in time of

our common ancestor - General physician and pharmacist

Academician p.m. (2003) Carol Davila is not only an

"energetic" man, but also an "energetic" spirit for those

around him, for all of us, when through his vision, calm and

analytical spirit, he manages to clarify things and "indicate"

the right direction to follow.

The release of the book, "Under the Sign of Hippocrates,"

was for all participants, as well as for future readers, a

celebration of the spirit.

The editorial staff of the

Romanian Journal of Military Medicine

Wishes

Happy Birthday!

To

Academician Victor Voicu

Honorary Editor


7

Article received on February 21, 2019 and accepted for publishing on June 11, 2019.

SYSTEMATIC REVIEW

Effect of the selective serotonin reuptake inhibitors over coagulation in patients with depressive disorders – a systematic review and retrospective analysis

Octavian Vasiliu1

Abstract: Several problems related to coagulation dysfunctions induced by selective serotonin reuptake inhibitors (SSRIs) were reported in literature, as serotonin is widely distributed in the human organism and it has significant contribution in various vascular and hematologic regulatory mechanisms. First, a systematic review has integrated main results from the field of SSRIs and anticoagulants pharmacologic interactions. Secondly, a retrospective analysis was performed, based on the medical charts of hospitalized patients diagnosed with SSRI-treated depressive disorders, who also received concomitant anticoagulant treatment with acenocoumarol. Platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time were monitored during hospitalization and their values before and after SSRI initiation treatment were compared.

Keywords: major depressive disorder, antidepressants, anticoagulants, serotonin

CURRENT STAGE OF RESEARCH IN THE FIELD OF SSRIs-

ANTICOAGULANTS INTERACTIONS AND SSRIs-INDUCED

COAGULATION DYSFUNCTIONS

Data in the literature regarding selective serotonin reuptake

inhibitors (SSRI) treatment in patients diagnosed with

depressive disorders and cardiovascular pathology for which

they receive anticoagulants contain contradictions regarding

the magnitude of antidepressants’ effect over coagulation

parameters.

Currently available informations suggest the existence of a

decrease in platelets serotonin due to serotoninergic

antidepressants action, and this phenomenon appears to be

explained by a pharmacogenetic mechanism, through

serotonin transporter promotor gene (5-HTTLPR) poly-

morphism [1, 2]. Also, it has been observed that serotonin-

nergic antidepressants could mitigate the depression- and

anxiety-related procoagulant action [3], while yet another

studies reveal the lack of significant effect of sertraline over

coagulation in patients after an acute myocardial infarction

[4].

An independent analysis of clinical trials published in the

main electronic databases (PubMed, Cochrane, Medscape,

and EMBASE), using keywords “anti-depressant”, “serotonin

selective reuptake inhibitors”, “major depressive disorder

(MDD)”, “coagulation”, “anticoagulants”, “paroxetine”, ”ser-

traline”, “escitalopram”, “citalopram”, “fluoxetine”, “fluvo-

xamine”, “warfarine”, and “acenocoumarol” was performed.

Only articles published between 1996 and 2018 have been

selected.

Specific inclusion and exclusion criteria had been formulated

according to Table 1.

1 Dr. Carol Davila University Central Emergency Military Hospital, Bucharest, Romania

Corresponding author: Octavian Vasiliu MD

[email protected]

8

Table 1. Selection criteria for literature research

Operationalized criteria Inclusion criteria Exclusion criteria

Population Inferior age limit is 18, no superior limit had been esta-blished. Diagnoses of MDD, dysthymia, adjustment disorder with depressive features, bipolar depression, mixed depressive and anxious disorder. Diagnoses according to DSM, ICD criteria, or compatible with these classifications. Lack of substance related comorbidities.

Children and adolescents. Heterogenous populations, where statis-tical procedures didn’t allow a separate conclusion for patients aged over 18. Other disorders than those with a signi-ficant depressive component

Intervention Any agent from the SSRI class. Monitored anticoagulant treatment.

Other, non-SSRIs-antidepressants. SSRIs in combination with other anti-depressants. Concomitant use of CYP450 iso-enzymes inductors or inhibitors. Supra-therapeutic doses of SSRI agents.

Environment In-patient or out-patient. In vitro or in vivo analysis of coagulation variables.

Unspecified environment.

Primary and secondary variables

Any coagulation-related indicator, like platelet count, bleeding time, prothrombin time etc. Discontinuation of treatment due to severe adverse events from the hematological domain, like gastro-intestinal bleeding, hemorrhagic stroke etc.

Any trial without coagulation related parameters as primary variables was excluded

Design Randomized clinical trials, open-label, single-blind or double-blind, placebo-controlled or not, prospective or retrospective trials, case control studies, case reports or case series.

Unspecified design. Lack of a specific method for coagulation monitoring

Language English, French, German, Romanian Other language except for those mentioned

A number of 9 trials corresponded to these criteria and were

included in analysis. A synthetic overview of the selected

studies is presented in Table 2.

Table 2. Synthetic indicators for selected trials

Overall number of subjects

Mean duration of interaction

Age at inclusion

n=391 43.4

SD=70.9 Minimum=1

Maximum=225

n=2 7.5 weeks

SD=6.3 Minimum=3

Maximum=12

n=3 68 years old

SD=19.9 Minimum=45 Maximum=80

Due to the fact that not all of the papers published contain

complete data, synthetic indicators were calculated using

only those studies which included specified variables, like

the number of participants, mean duration of treatment or

the patients’ age at inclusion.

The most relevant research data are presented in Table 3.

SSRIs as a pharmacologic class induced lower serotonin

levels in the patients’ platelets [1] and had a significant effect

over several indicators of coagulation [3].

Fluoxetine increased significantly the bleeding time,

although not above the normal values [5]. Another trial

showed no significant influence of fluoxetine over mean

prothrombine time during warfarin treatment [6].

Escitalopram had no effect on coagulation according to one

trial [5].

Fluvoxamine could induced an over-anticoagulation status

during acenocoumarol maintenance treatment, unlike other

SSRIs used as controls [7]. Fluvoxamine effect over

coagulation is supported also by two cases treated with

warfarine [8, 9].

Sertraline is relatively safe in patients after acute MI, as it

induced no changes in bleeding time [4]. Sertraline could

interfere with warfarine at circulating binding proteins and

displaced the anticoagulant, increasing its free fraction [10].

In conclusion, escitalopram, sertraline and fluoxetine seem

to be quite safe during anticoagulant treatment, while

fluvoxamine has a tendency for inducing an over-

anticoagulation status. Not enough data have been found to

formulate a conclusion regarding paroxetine and citalopram,

but these agents seem safer than fluvoxamine, in trials who

compared various serotoninergic agents. SSRIs, as a

pharmacological class, doesn’t induce significant effects over


9

coagulation from a clinical point of view.

Table 3. Studies included in the systematic review

AUTHORS DESIGN RESULTS AND OBSERVATIONS

Reikvam AG, Hustad S, Reikvam H, et al., 2012 [1]

Case-control pilot study. In vitro measurements of platelet function. N=18. Blood donors using SSRIs vs. blood donors without treatment

Donors with SSRIs had significantly lower serotonin in their thrombocytes. Coagulation could be altered in patients using SSRIs based on lower serotonin platelet concentration.

Siddiqui R, Gawande S, Shende T, et al., 2011 [5]

Prospective, open-label, diagnosis of MDD. Bleeding time, clotting time, platelet count, prothrombin time, partial thromboplastin kaolin time – all were monitored for 12 weeks. N=40. Treatment with fluoxetine or escitalopram

At week 12 a significant increase in bleeding time was detected for fluoxetine, while escitalopram had no effect on coagulation variables. Fluoxetine is more powerful inhibitor of SERT than escitalopram. Fluoxetine increased significantly the bleeding time, but not beyond the normal values

Geiser F, Conrad R, Imbierowicz K, et al., 2011 [3]

Case-control study. Anxiety and comorbid depression. APTT, fibrinogen, factor VII, factor VIII, von Willebrand factor, von Willebrand ristocetin cofactor activity, prothrombin fragment 1 and 2, thrombin-antithrombin complex, d-dimer, alpha2-antiplasmin, PAP, tissue plasminogen activator and plasminogen activator inhibitor. N=62.

Fibrinogen, plasminogen activator inhibitor, PAP differentiated SSRIs treated patients from their matched controls. After controlling for smoke status and BMI, differences between groups were significant for PAP, von Willebrand ristocetin cofactor activity and APTT. Several coagulation indicators may be affected at significant levels (p<0.05) in anxious-depressive patients treated with SSRIs

Teichert M, Visser LE, Uitterlinden AG, et al., 2011 [7]

Prospective, populational-based cohort study. INR≥6 was the event monitored in patients treated with SSRIs during acenocumarol maintenance treatment. N=225 Age ≥ 45

The risk for over-anticoagulation during acenocoumarol maintenance treatment was increased in patients treated with fluvoxamine, but not with other SSRIs. Prothrombine time in users of acenocoumarol was increased by fluvoxamine above a critical value associated with bleeding risk. Number of exposed patients to other SSRIs except for fluvoxamine was low.

Limke KK, Shelton AR, Elliott ES, 2002 [8]

Case report. Warfarin+fluvoxamine 79 year old woman

Increased values of INR that persisted for 7 days. Fluvoxamine inhibits CYP1A2, 2C9, 2C19 and 3A4, while the metabolism of warfarine involves the same isoenzimes of CYP450.

Yap KB, Low ST, 1999 [9]

Case report. Warfarin + fluvoxamine. 80 year old woman

The interaction between fluvoxamine and warfarin could persist for up to 2 weeks after stopping the antidepressant

Shapiro PA, Lesperance F, Frasure-Smith N et al., 1999 [4]

Multicenter, open-label, pilot study. MDD patients identified 5 to 30 days after admission for acute MI. Serial bleeding time determinations. N=26

Bleeding time increased in 12 patients, decreased in 4 patients, was unchanged in 2 patients, 3 patients withdraw prematurely. No significant changes in coagulation measures. Sertraline seems to be relatively safe in patients after acute MI.

Ford MA, Anderson ML, Rindone JP, Jaskar DW, 1997 [6]

Open label. Stable dose of warfarin + fluoxetine. Prothrombine time was measured during the 22 days of the trial. N=6

No significant differences in mean prothrombine time before and during fluoxetine administration were detected. Fluoxetine at 20 mg/day doesn’t influence the hypopro-thrombinemic response of warfarin.

Apseloff G, Wilner KD, Gerber N, Tremaine LM, 1997 [10]

Non-blinded, randomised, placebo-controlled. Healthy male volunteer. Warfarin+sertraline or placebo. N=12

Increased prothrombine time significantly during sertraline versus placebo (p=0.02). After 22 days a significant increase (p=0.02) in unbound warfarine was observed in sertraline vs. placebo group. Differences between groups were statistically, but not clinically significant. Sertraline has minimal effect on the CYP2C9/10 isoenzyme, while warfarin is principally mediated by this enzyme.

SERT = serotonin transporter, BMI = body mass index, APTT = activated partial thromboplastin time, PAP = plasmin-alpha2-antiplasmin complex, INR = International

Normalised Ratio, MI = myocardial infarction

10

Nevertheless, pharmacokinetic interactions between SSRIs

and anticoagulants are possible, at the plasma protein

binding level and at the CYP450 isoenzymes level, therefore

monitoring of the main coagulation parameters is

recommended in patients who undergo serotoninergic

antidepressant and anticoagulant treatment.

RETROSPECTIVE ANALYSIS IN PATIENTS USING SSRIs AND

ANTICOAGULANTS

Patients diagnosed with depressive disorders admitted in

the hospital who received an SSRI agent, and who also were

diagnosed with various cardio-vascular or hematologic

diseases for which they received anticoagulant treatment,

were analysed from coagulation parameters perspective.

Objective

To detect if significant statistical and/or clinical variation of

coagulation variables are detected during combined, SSRIs

and anticoagulant treatment.

Methods

We analyzed retrospectively charts of all patients evaluated

for depressive disorders during one year in our department

(01 January 2017 – 31 December 2017), which had anti-

coagulant treatment with acenocoumarol and also received

treatment with escitalopram, citalopram, fluoxetine,

paroxetine, fluvoxamine or sertraline. Platelet count,

prothrombin time as reflected in the INR values, APTT, and

bleeding time were analyzed in all cases which were

monitored during hospitalization and their values before and

after SSRI initiation treatment were compared.

All included patients were over 18 years old, without

previous treatment with an SSRI agent and were stabilized

on acenocoumarol at time of the admission. Depressive

disorders diagnoses were formulated according to ICD-10

criteria and included MDD, either first episode or recurrent,

bipolar depression, dysthymia, adjustment disorder with

depressive manifestations, mixed anxious-depressive

disorder.

Patients diagnosed with comorbid substance related

disorders were excluded from this analysis, and also those

with mentioned history of non-adherence to their

anticoagulation treatment.

Results

A number of 42 patients, mean age 56.6, 30 female and 12

male, diagnosed with MDD (n=23), mixed anxious-

depressive disorder (n=10), bipolar depression (n=4),

dysthymia and MDD (n=2) and adjustment disorder with

depressive manifestations (n=3) were included in the

statistical analysis. These patients had at least two

determinations of INR and platelet count in their charts and

most of them (62%) had at least 3 coagulation indicators

recorded.

Figure 1: Treatment used during anticoagulation therapy

Patients received escitalopram (n=11), citalopram (n=2),

paroxetine (n=10), sertraline (n=8), fluoxetine (n=8) or

fluvoxamine (n=3).

Figure 2: SSRIs treatment influence over coagulation indicators

(% of score variation)

No significant differences (at p<0.05) were detected in any

coagulation indicator for SSRIs as a pharmacologic class, as

reflected by t test for dependent samples, when platelet

count (p=0.166), INR (p=0.098), APTT (p=0.110), and

bleeding time (p=0.102) were analyzed pre-SSRIs

administration and after at least 7 days (mean duration of

SSRIs treatment before hospital discharge was 8.4 days).

When translated in percentage of absolute values variation,

all SSRIs changes ranged from 5 to 10% in all the monitored

parameters.

ANOVA univariate test resulted in F values ranging between

1.67 and 1.28, lower than Fcrit, at p<0.05, and η2 varied

between 0.025 and 0.069, which signifies an influence of 2.5-

6.9% of the SSRIs agent over INR, APTT, bleeding time, and

platelet count variation during acenocoumarol treatment. A


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post-hoc analysis showed a superior effect over bleeding

time for fluvoxamine over escitalopram and sertraline

(p=0.043 and 0.46), although the clinical impact of this

difference wasn’t relevant.

No significant adverse event in the hematologic area was

recorded during hospitalization period and mixed (SSRI and

anticoagulant) treatment.

Two cases (one treated with fluvoxamine 150 mg/day and

one who received paroxetine 40 mg/day) registered values

of INR above therapeutic value (5.2 and 6.1, respectively)

after 8 days of treatment, and acenocumarol doses were

adjusted.

CONCLUSIONS

SSRIs had a minor influence over main coagulation

parameters (INR, APTT, platelet count, and bleeding time)

during acenocoumarol treatment in patients with depressive

disorder and comorbid cardio-vascular or hematologic

diseases.

Fluvoxamine has been associated statistically with a lesser

safe profile than escitalopram and sertraline, although

differences in the clinical domain are not detectable.

Disclaimer

Octavian Vasiliu was speaker for Servier and Bristol-Myers, and

participated in clinical trials funded by Janssen Cilag, Astra Zeneca,

Otsuka Pharmaceuticals, Sanofi-Aventis, Sunovion Pharmaceuticals.

Ethical considerations

All the analyzed medical charts included patients’ informed consent

for processing of their personal data for research and educational

purposes.

List of abbreviations

5-HTTLPR= Serotonin-transporter-linked polymorphic region

APTT= Activated partial thromboplastin time

APTT= activated partial thromboplastin time,

BMI= body mass index

DSM= Diagnostic and Statistical Manual of mental Disorders

ICD= International Classification of Diseases

INR= International normalized ratio

MDD= major depressive disorder

MI= myocardial infarction

PAP= plasmin-alpha2-antiplasmin complex

SERT= serotonin transporter

SSRI= Selective serotonin reuptake inhibitor

References:

1. Reikvam AG, Hustad S, Reikvam H, et al., The effects of selective serotonin reuptake inhibitors on platelet function in whole blood and platelet concnetrates. Platelets 2012;23(4):299-308.

2. Abdelmalik N, Ruhe HG, Barwari K, et al., Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost 2008;6(12):2168-74.

3. Geiser F, Conrad R, Imbierowicz K, et al., Coagulation activation and fibrinolysis impairment are reduced in patients with anxiety and depression when medicated with serotoninergic antidepressants. Psychiatry Clin Neurosci 2011;65(5):518-25.

4. Shapiro PA, Lesperance F, Frasure-Smith N, et al., An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 1999;137(6):1100-6.

5. Siddiqui R, Gawande S, Shende T, et al., SSRI-induced coagulopathy: is it really? Ther Adv Psychopharmacol 2011;1(6):169-

74.

6. Ford MA, Anderson ML, Rindone JP, Jaskar DW, Lack of effect of fluoxetine on the hypoprothrombinemic response of warfarin. J Clin Psychopharmacol 1997;17(2):110-2.

7. Teichert M, Visser LE, Uitterlinden AG et al. Selective serotonin re-uptake inhibiting antidepressants and the risk of overanticoagulation during acenocoumarol maintenance treatment. Br J Pharmacol 2011;72(5):798-805.

8. Limke KK, Shelton AR, Elliott ES, Fluvoxamine interaction with warfarin. Ann Pharmacother 2002;36(12):1890-2.

9. Yap KB, Low ST, Interaction of fluvoxamine with warfarin in an elderly woman. Singapore Med J 1999;40(7):480-2.

10. Apseloff G, Wilner KD, Gerber N, Tremaine LM, Effect of sertraline on protein binding of warfarin. Clin Pharmacokinet 1997;32(Suppl.1):37-42.

12

Article received on May 20, 2019 and accepted for publishing on June 21, 2019.

REVIEW ARTICLE

Improved methodology of using simulators develops better practical skills in laparoscopy of future residents

Cristian V. Toma1,2, Cristian S. Sima1,2, Daniel G. Radavoi1,2, Traian Constantin1,2, Daniel L. Bădescu1,2, Viorel Jinga1,2

Abstract: Background and aim: Minimally invasive surgery represents the actual tendency in many medical domains including urology. Gaining practical skills for these procedures becomes essential when preparing the future resident physicians in urology. The purpose of this study is to demonstrate that using medical simulation as an education tool improves the practical skills of the urology house officers in laparoscopy by using an accessible tool such as a box trainer.

Methods: The study includes the objective and subjective evaluation of the practical skills of 54 students with no experience in laparoscopy. Each participant was evaluated before doing the practical activity on the simulator both in a subjective manner by filling a self-evaluation form and also objectively by timing the duration of doing laparoscopic basic tasks, knot tying and realizing a continuous suture. The participants were divided in two groups (A-28 participants, B-26 participants). Each group executed the same procedures with the same instruments, but with a different teaching technique.

Results and conclusions: Medical education with the help of a laparoscopic box trainer simulator is a useful tool for improving practical abilities and the time of execution of general procedures.

Keywords: medical education, laparoscopy, box trainer simulator, students, methodology

INTRODUCTION

On a continuous way to become an overall gold standard

laparascopy and minimally invasive surgery in general shows

better results in terms of patient recovery, hospitalization

period, and fewer complications such as blood loss or side

effects due to less required analgesia when compared to

large open incisions [1]. Minimally invasive surgery also gives

the advantage of smaller wound infection rates [2], fewer

dehiscence rate and incisional hernia [1]. Key whole surgery

requires more time, energy and financial resources. For

example, the learning curve for laparoscopic radical

prostatectomy was slower than the previously reported

learning curves for open surgery [3]. All of these are due to

less tactile real feel, loss of depth understanding, fulcrum

effect and also due to manipulation: hand-eye coordination.

Young urologists, especially residents, should be better

prepared before performing their first interventions and this

can be done in a safe, repeatable environment with the help

of medical simulation.

Basic and essential skills such as camera manipulation,

moving objects, manipulating intracorporeal materials (i.e.

gauzes, tissue), knotting and suturing, tissue manipulation

can be trained using medical simulation. In laparoscopy

medical simulation can be trained with the help of basic

pelvic trainers, virtual simulators which can also help

improve procedural steps and live surgery on animal tissue

such as porcine models.

The most reproducible, accessible and economic way of 1 “Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest, Romania 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Corresponding author: Cristian V. Toma MD

[email protected]


13

teaching laparoscopy to beginners is with pelvic trainers/box

trainers. Unlike open surgery where one can encounter

more learning possibilities, laparoscopic training for young

surgeons is a challenge in their formation.

Training with the help of medical simulation has the purpose

to transfer the acquired skills in the operating room [4]. In

order to establish a minimum standard of training the

European Society of Urology established a model called E-

BLUS European Basic Laparoscopic Urologic Skills.

This model has a set of validated exercises which are

applicable in urologic laparoscopic procedures. In addition to

repeating the video showed skills one can improve the

learning curves by identifying possible factors without taking

into account the native ability of the surgeon or his previous

surgical experience. [5] “And therefore I find that being a

surgeon is a vocational profession, such as the athletes and

airplane pilots” [6] thus meaning that the surgeon should

also exercise before passing to real life scenarios, exactly

how pilots train on advanced simulators in order to perfect

their skills.

OBJECTIVE

To assess the better methodology of learning basic urologic

laparoscopic skills by medical students using a box trainer.

METHODS

A study was realized with 54 medical students from all years

of study from the University of Medicine and Pharmacy

“Carol Davila” from Bucharest through from January 2017 to

November 2018. The participants signed an informed

consent and completed forms requiring basic demographic

data such as age, year of study, gender, will to pursuit

surgical careers and dominant hand.

The participants were divided in two groups. Group A had 28

students who were trained within 3 separate workshops (10,

9, 9) following one simple metho-dology; group B contained

26 participants who were divided in 3 separate workshops

(10, 8, 8) and followed a more explicit and didactic

technique.

All of the participants had to do the E-BLUS exercises. The

first time they realized each exercise they were timed and

after 15 minutes of practice they repeated the same

measurement. The selected time was 15 minutes in order to

have enough time, energy and concentration for the

students to perform the tasks.

The instructors were represented by either urologists or

general surgeons with laparoscopic experience. Pedagogical

skills of the instructors were a criteria for inclusion in the

study. All of the instructors who were part of the project had

to train other senior students or residents with the aim of

forming bench side instructors who would facilitate the

communication between participants and main instructor

and also give technical and logistic aid to the participants.

Tasks

The European training in Basic Laparoscopic Urological Skills

consists of an online theoretical course which is followed by

realizing 4 tasks in a specific amount of time. The tasks and

their demo version can be found on the uroweb.org website.

[7]

The tasks that were shown to GROUP A were similar to the

ones from the E-BLUS. Peg transfer and circle cutting were

identical. Needle guidance was observed in previous

workshops to discourage students due to its difficulty and

high energy consumption so we decided to take a thicker

thread/suture without a needle so it would be easier to

manipulate, but maintain the same rotation, piston like and

hand eye coordination requirement. The laparoscopic

suturing exercise was divided in two sub-tasks. The first one

was to make a laparoscopic intracorporeal surgical knot,

while the second one required for the volunteers to realize a

surgical knot, make 3 sutures and then close with a second

knot on a silicon model [8].

The methodology for group A was the following: instructor

delivered two 15 minutes presentations on laparoscopy in

general and laparoscopic instruments, after these all of the

procedures were shown one by one by the main instructor

at the demo pelvic trainer and immediately after the

participants repeated each procedure with measuring the

initial time and the after 15 minutes training timing.

Group B on the other hand repeated the same exercises,

received the same live demonstration and video support. In

addition to these, each of the exercise except circle cutting

had a 3 minute training session with different exercises. Peg

transfer exercise was preceded by lifting 6 pin board pins one

by one, passing them from one instrument to the other and

placing them in a plastic recipient. The thread passing

exercise was preceded by a 3 minutes exercise which

required passing of an articulated metal piece through a

fixed orifice.

The breakthrough of this project besides improving the

laparoscopic skills of all students was the significant

improvement in time for the knot and suturing part of the

workshop for Group B. The participants from Group B were

made to repeat the intra-corporeal knot with the

laparoscopic instruments under direct vision after the initial

timing was measured.

14

This was done by disconnecting the monitor and changing

the “abdominal wall” from the pelvic trainer with a

transparent plastic sheet. In this way the movements were

maintained restrained by the trocars, but the conversion

from 2D to 3D natural view was present.

As a result the students at a cognitive level saw the

procedure under 3D circumstances and when conversion to

conventional 2D laparoscopic conditions was made the

overall final improvement was significant as it will be shown

in the results section.

RESULTS

The average year of study was 3.58, the male-female ratio

was 1:1.4, and none of them had previous laparscopic

surgery experience. All of the presented times are median

scores over the same sector. All of the 28 scores of Peg

Transfer Before section were summed and then divided by

28. The same principle was applied to all sections. The Time

Difference column shows the performance in time before

the Group B and Group A.

Figure 1: Comparison between groups

As one can see in Table 1 there is no significant difference in

the before timing of the majority of exercises besides

knotting and suturing which was enhanced in Group B

probably due to the technique of showing the tasks under

natural view and than reproduce the gestures and steps

combining 3D cognitive perception with 2D laparoscopic

vision.

Table 1: Overall timing in both groups A and B

Task Group A Group B Time Diference Significant3

1. Peg Transfer Before 5:24 5:45 -0:21 No

Peg Transfer After 3:22 2:11 1:11 Yes

2. Thread Passing B1 5:31 5:32 -0:01 No

Thread Passing A2 3:07 2:07 1:00 Yes

3. Knot B 12:55 10:58 1:57 Yes

Knot A 9:14 4:47 4:27 Yes

4 Suture B 21:59 13:26 8:33 Yes

Suture A 16:03 8:49 7:14 Yes

5 Circle Cutting B 5:28 5:14 0:14 No

Circle Cutting A 3:26 3:24 0:02 No

1B – before 2A – after 3Significant – more than 59 seconds difference

There was no significant difference in the Circle cutting

group due to the fact that no extra exercise or technique was

used in the Group B in order to enhance the performance.

In group B there was significant difference even in the

“before” timing of knots and sutures probably due to the

enhanced abilities given by the two extra exercises.

The overall extension of the Group B training time given by

the three extra exercises of three minutes each was of nine

minutes in practical extra activity and 21 minutes required

to change the materials within the pelvic trainer.


15

Figure 2: Comparison – linear interpretation

DISCUSSION

The timings could have been improved if the participants

would have had more ergonomic instruments. All of the

instruments had finger rings – Mayo Hegar laparoscopic

needle holder.

Due to technical possibilities the table on which we placed

the pelvic trainers had the same height which was

inappropriate for short or tall students. Step stools were

given to short students, but not offering them the best

conditions. Tall students had the same problem.

The three speakers who took part in this project had two

presences- one for group A and one for Group B. The sub-

instructors were the same along the entire project.

CONCLUSION

It is well known that medical simulation in laparoscopy has

its role in reducing the necessary time to acquire basic

urologic skills in a safe and repeatable environment without

the stress and pressure felt in operating room. This study

demonstrates that even simple methodology can enhance

the beginner’s basic laparoscopic skills. In addition, due to

experience, medical professional who teach these type of

procedures can accelerate the process with tips and tricks

which precede the proposed measuring tools. In this way the

time from transferring the skills from laboratory to the

operating room can be shortened and overall confidence of

the surgeon can be enhanced.

Disclaimer

Nothing to declare. No financial grants or other funding were used.

Aknowledgements: Medical Simulation Center “LifeSim”, Bucharest

for offering the box trainers and space.

References:

1. Henry MM, Thompson JN. Clinical Surgery. London: W B Saunders, 2001

2. Daniar K.Osmonov et al, Turk J Urol. 2018 Jul; 44(4): 303–310.

3. Andrew J Vickers et al, Lancet Oncol. 2009 May; 10(5): 475–480

4. Bonrath EM, Weber BK, Fritz M, Mees ST, Wolters HH, Senninger N, Rijcken E Surgery. 2012 Jul; 152(1):12-20.

5. Feldman LS, Cao J, Andalib A, Fraser S, Fried GM Surgery. 2009

Aug; 146(2):381-6.

6. Mischianu D - Being a surgeon - a terrible and fascinating job – RJMM, 2018 April, 25(4):3-4

7. http://uroweb.org/education/online-education/surgical-education/laparoscopy/

8. https://www.simulab.com/products/tissue-suture-pad-

package-0

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REVIEW ARTICLE

Current review of surgical management options for rotational alignment of the femoral and tibial component in total knee replacement

Bogdan Crețu1,2, Cătălin Cîrstoiu1,2, Ștefan Cristea1,3

Abstract: Rotational malalignment complication following TKA, is common but can be avoided with proper surgical technique. This paper reviews the literature regarding rotational alignment during TKA, femoral and tibial rotation, and highlights the techniques prior in obtaining proper rotational positioning, nevertheless correct positioning in all three planes is important.

Proper femoral component positioning in the axial plane is done using as landmarks the posterior condylar line (PCL), surgical transepicondylar axis (sTEA), anatomical transepicondylar axis and the trochlear anteroposterior (AP) axis. The paper describes the angular relationships between these landmarks and the distal femur. Axial tibial positioning is done when using intraarticular landmarks, the combination of more than one landmark could be a solution for solving this problem.

The consensus is that femoral component should be positioned according to TEA but the interobserver variability of this land mark is very high. The rotation of the tibial component remains an open subject, most studies suggesting a point between half of the distance of patellar ligament and 1/3 of the internal tuberosity as optimal landmark.

Keywords: total knee arthroplasty; femoral component rotation; tibial component rotation

INTRODUCTION

Total knee arthroplasty (TKA) is an intervention whose

efficacy in the treatment of gonarthrosis is well known and

documented [1]. The results of this intervention depend on

the correct positioning of the prosthetic components in all

three planes: frontal, sagittal, and axial [2]. The axial plane

within TKA is represented by the alignment of the prosthetic

components in the rotational plane. In 1979, Mochizuki and

Schurman, who have shown that a lateral force produces the

sprain of the patella when the tibial component is positioned

according to the posterior plateau, described the

importance of rotational positioning. They recommended

that the tibial component should be aligned with the tibial

tuberosity and the femoral component in a relative external

rotation to the tibia at the time of a complete extension [3].

Femoral component positioning errors in the axial plane lead

to complications in the femuropatellar joint, ligament

instability and changes in normal kinematics [4]. The

positioning of the tibial component from a rotational point

of view has not been as studied, but its importance is equally

large. The malposition of the tibial component is indirectly

responsible for the femuropatellar complications that are

often the cause of postoperative knee pain, reduced mobility

and early revision [5]. Although current instrumentation

methods have greatly reduced the malposition rate of

1 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 Department of Orthopedics and Traumatology, University Emergency Hospital, Bucharest, Romania 3 Department of Orthopedics and Traumatology, Pantelimon Emergency Hospital, Bucharest, Romania

Corresponding author: Bogdan Cretu, MD

[email protected]


17

components, the subject of rotation is not a closed one, and

there is no consensus for the perfect positioning.

In this paper, we will try to present a review of recent

literature on the correct rotational positioning of the

femoral and tibial component, to describe the different axes

guiding the rotational alignment, and to compare the known

techniques.

ROTATION OF FEMORAL COMPONENT

The correct positioning of the femoral component from a

rotational point of view is an important step for the success

of TKA. The positioning of the femoral component in axial

plane has repercussions on stability in flexion, knee

kinematics, flexion alignment and femuropatellar joint [6, 7].

Berger demonstrated the relationship between the internal

rotation of the femoral component and the patellar

maltracking [8]. He was the first to use the CT to evaluate the

rotation of prosthetic components. He showed that a low

internal rotation, between 1 and 4o would lead to patellar

maltracking and tilting, an average internal rotation,

between 5 and 8o would lead to subluxation and a severe

internal rotation of 7-17o, would lead to the sprain of the

patella. For the analysis of both femoral and tibial rotation,

Berger used the transepicondylar axis (TEA) and tibial

tuberosity as anatomical landmark.

The external rotation of the femoral component also has

negative repercussions on the TKA. Olcott et al. have shown

that with the increase of external rotation of the femoral

component, the medial flexion space increases, the result

being a flexion instability symptomatology [9]. Another

study led by Hanada et al. has shown that the excessive

external rotation of the femur leads to varus flexion, the

result being an excessive loading of the external

compartment [10].

The consequences of external femoral rotation are well

known; the best landmark for a good rotation is a topic yet

debated. Many landmarks and axes have been described at

the level of distal femur: posterior condylar line (PCL),

transepicondylar axis (TEA), surgical transepicondylar axis

(sTEA), anteroposterior axis (AP) or Whiteside line anterior

femoral axis [11, 12].

“Tension gap” technique

The purpose of this technique is that after creating the gaps,

the flexion space should be rectangular and equal to the

extension space [13]. The soft parts of the knee are first

balanced in complete extension by ligament rebalancing and

subsequently at 90o flexion, either manually or with a

laminar spreader. The aim is to obtain equal ligament

tension both internally and externally and, after creating the

posterior femoral cuts, the posterior femur should be

parallel to the tibial surface after proximal tibial resection so

that this space is rectangular. To support this theory, Laskin

compared two groups of patients, in one group, the size of

posterior femoral cuts was equal, and in the second group,

the resection plane of posterior condyles was externally

rotated to obtain a rectangular space. He noted that for this,

it is necessary that the posterior medial femoral cut is larger

than the lateral one, with a relative increase of this

difference in the valgus knees due to lateral femoral

condylar hypoplasia. The average external rotation for

flexion space rectangulation was 3.20 to the posterior

condylar line [14].

Correct valgus or varus extension positioning is a problem

solved by current instrumentation systems but varus or

valgus flexion alignment is often forgotten. This problem was

investigated in a cadaver study, in which they compared the

“tension gap” technique with the anteroposterior axis

(Whiteside’s Line). Using the “tension gap” technique, they

noted that they had good stability in extension and flexion,

but the knees had varus deviations at flexion with an average

of 8.2 , increasing pressure in the internal compartment.

This phenomenon is largely due to the lateral collateral

ligament, which in a normal knee is slightly laxer than the

medial, this allowing the tibia to be pushed into varus

(allowing the internal rotation of the femur against the tibia)

when using the tensioning methods of equalizing the

tensions between the two ligaments [15]. In the group in

which the antero-posterior axis was used, the results were

better in terms of stability and alignment.

Transepicondylar axis (TEA)

It is defined as a line crossing the two epicondyles, medial

and lateral. This approximates the flexion-extension axis of

the knee [16]. The positioning of the femoral component in

the axial plane according to this line leads to an optimal

patellar tracking, decreases the shearing forces at the

beginning of flexion, and decreases the use of polyethylene

insert. Internal or external rotations to this axis will result in

changes in the patellar tracking [17]. The defect of this axis

is that it cannot be located accurately intraoperatively.

Berger et al. examined the knees of 75 cadavers and came to

the following conclusions: surgical TEA is the axis between

the lateral epicondyle and the medial sulcus, a channel

below the medial epicondyle [18]. They concluded that the

medial sulcus was an easily identifiable anatomical landmark

and measured the difference between surgical TEA and the

posterior condylar line as being 3.5○ in males and 0.3○ in

females. After studying 32 cadavers, Yoshioka et al.

concluded that there is a “condylar twist angle” of 5○ in

18

males and of 6○ in females [19]. Although TEA is an axis

difficult to highlight during surgery, especially in cases of

significant destructive changes or in revisions, it could be the

most accurate landmark for determining the rotation of the

femoral component.

Posterior condylar line (PCL)

Using the posterior condylar line as a landmark for

determining the femoral rotation is a well-known and

generally accepted technique. PCL is on average 3-5○ in

internal rotation than TEA [20]. Most of the TKA instruments

kits have additional pieces for external rotation attached to

the instrument that palpates the posterior condyles, which

try to position the two pins of the femoral cutting block

parallel to TEA. In examination, PCL is identified by

digitization and the desired external rotation is added to it.

Different studies highlighted that optimal patellar tracking

was obtained with external rotation of the femoral

component. Patients with the femoral component in

external rotation do not need a rebalance of the extensor

retinaculum and have better postoperative patellar tracking.

This classic technique of positioning the femoral component

in external rotation is easy to use but has the disadvantage

that posterior condyles have to be perfectly palpated. This is

not always possible due to the size differences of posterior

condyles especially in cases of genu valgus with lateral

femoral condylar hypoplasia in which there is a risk of

internal rotation of the femoral component.

Trochlear anteroposterior (AP) axis

Also called the Whiteside line, the trochlear anteroposterior

(AP) axis was originally described as a landmark in

unicompartmental arthroplasty [21]. It was later used as a

landmark for the positioning of the femoral component in

axial plane in valgus deviation knees. It is defined as a line

that joins the deepest point of femoral trochlea with the

center of the deep lateral femoral notch. The perpendicular

line on the AP axis is about 4○ of external rotation compared

to PCL. TEA has an average of 4.4○ of external rotation

compared with AP axis. The AP axis has the advantage of

being easy to use and it can be identified during basic TKA.

TIBIAL COMPONENT ROTATION

The tibial component rotation is at least as important as the

rotation of femoral component. The positioning of the tibial

component in axial plane is responsible for optimal patellar

tracking. An internal rotation will lead to a lateralization of

tibial tuberosity and an increase of Q angle that will

predispose to the subluxation of the patella [22]. The

optimal tibial component position is not known exactly but

we know that higher revision rates occur, and the clinical

results are weaker at the time of malposition of the tibial

component [23]. Many intra- and extra-articular landmarks

are known. Intra-articular landmarks are tibial tuberosity,

patellar ligament, and posterior tibial axis. There is also an

option of alignment with the femoral component implanted

according to TEA in extension [24]. Another option is to place

the tibial component so that we have maximum tibial

coverage [25]. The extra-articular landmarks are the

transmalleolar axis of the ankle and the metatarsal II axis.

The decision regarding what type of landmark to use for the

axial alignment of the tibia is a difficult one and is influenced

by other intraoperative factors. The external rotation of the

plateau increases when an external parapatellar approach is

used and an incomplete tibial plateau exposure resulting in

internal rotation of the plateau [26].

Finding the optimal rotation of the tibial plateau requires a

deep understanding of knee kinematics. In a normal knee,

the tibia makes an internal rotation motion at the time the

knee is in flexion and an external rotation motion at the end

of the extension. This mechanism of external rotation at the

end of the extension is called “screw home mechanism”, due

to the geometry of the joint surfaces combined with the

cruciate ligaments [27].

This physiological movement occurs between 0 and 15○ of

flexion. Often, this mechanism sometimes disappears, is low

or paradoxically appears after TKA [28]. To reduce

polyethylene use, we need to obtain a better axing of the

two components in axial plane after TKA. The aim is to have

a neutral rotation between the two components during the

entire flexion, the rotational gap leading to femorotibial

subluxation and early destruction of the polyethylene

insertion.

Extra-articular landmarks

The most known extra-articular anatomic landmarks for

rotation positioning of the tibial component are the

transmalleolar axis of the ankle and the metatarsal II axis.

Both axes have a significant variability in their knee

orientation in different individuals [29]. In conclusion, these

landmarks should not be the only ones used to determine

the rotation. Extra-articular deformities secondary to

trauma or arthrosis may result in alteration of these

landmarks relative to the knee [30].

Intra-articular landmarks

Anterior tibial tuberosity is the most commonly used

anatomical landmark for the proper determination of tibial

plateau rotation. It is a landmark easy to identify and is not

modified by gonarthrosis. This anatomical structure was split


19

to increase the efficiency of its identification and its use. To

determine the rotation, the internal edge of the tuberosity

and 1/3 of the internal tuberosity are used [30].

In a study using the CT, the medial edge of the tuberosity was

used in a lot of patients and in the second lot of patients, 1/3

of the internal tuberosity was used for the positioning of the

tibial plateau in axial plane. The femoral component in all

patients was positioned according to TEA. In the lot of

patients in which 1/3 of the internal tuberosity was used as

landmark, the femorotibial gap was lower, 67.5% of the

patients between ±5○, 85% between ±10○ and 97.5%

between ±20○, compared to the lot of patients in which the

medial edge of tuberosity was used, 3.8% of the patients

between ±5○, 15% between ±10○ and 68.8% between ±20○.

In conclusion, the authors support the use of 1/3 of the

internal tuberosity as landmark for the positioning of the

tibial plateau [31].

Another study evaluated the relationship between TEA, the

patellar ligament, and the posterior tibial axis in 30 healthy

patients by MRI [32]. They found that the perpendicular line

on TEA intersects the middle of the patellar ligament, the

intersection being at about 41% of the width of the tendon

measured from its internal edge. In order to have a smaller

gap between the femur and the tibia, the anteroposterior

axis of the tibial component must intersect the patellar

ligament and the femoral component aligned with the TEA.

This technique will finally result in a lack of coverage of the

posteromedial tibia of about 5 mm with a variation between

2 and 10 mm. The patellar ligament is not modified by

gonarthrosis, but its width is variable depending on the

surgical approach. When the tibial plateau is positioned

depending on the posterior cortex, it will enlarge the tibia

coverage, but will also greatly raise the rate of the internal

rotation of the tibial plateau. The authors of the study

concluded that the optimal landmark is an immediate point

located medial to the patellar ligament. The normal

anteroposterior diameter of the tibial plateaus is different,

and this will lead to the highlighting of the posteromedial

bone at the time the tibial plateau is positioned correctly.

“Self-seeking” method

This method involves introducing trial components and

performing full flexion and complete extension. The trial

tibial plateau will be rotationally positioned according to the

femoral component. The center of the trial tibial component

is marked with the electrocautery and the final implantation

is made using this point as landmark. This technique depends

on the correct positioning of the femoral component, in

femoral malrotation, the tibial component will also be

affected. There is a risk that, when the femoral component

is positioned in internal rotation and the tibial plateau is

internally rotated, major problems of patellar tracking occur

together with an increased instability. In order to overcome

this problem and at the same time to use it, it is

recommended to use a mobile plateau that will rebalance

the tibiofemoral gap.

The mobile tibial plateau or “mobile-bearing” was built so

that the polyethylene insertion follows the femoral

component in rotation and the tibial component in flexion-

extension. “Mobile-bearing” TKA reduces the need for tibial

component placing in a perfect rotation and reduces the gap

between the tibia and the femur. The disadvantage is that a

second joint surface is created between the insertion and

the tibial plateau and the destruction of polyethylene can

occur at both interfaces.

CONCLUSIONS

TKA function and survival depend on an optimal rotation of

the femoral component but also of the tibial component.

The positioning of the femoral and tibial component is well

known in the sagittal and frontal plane, but it is not very clear

in the axial plane. There is a consensus that the femur should

be positioned according to TEA but the methods this would

be possible are not optimal. The combination of different

techniques and the use of many landmarks could be a

solution. The rotation of the tibial component remains an

open subject, most studies suggesting a point between half

of the distance of patellar ligament and 1/3 of the internal

tuberosity as optimal landmark.

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6. Oussedik S, Scholes C, Ferguson D, Roe J, Parker D. Is femoral component rotation in a TKA reliably guided by the functional flexion axis? Clin Orthop Relat Res. 2012 Nov;470(11):3227-32. doi: 10.1007/s11999-012-2515-0. Epub 2012 Aug 16.

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8. Berger RA, Rubash HE, Seel MU, et al. Determining the rotational alignment of the femoral component in total knee arthroplasty using the epicondylar axis. Clin Orthop. 1993;286:40-7.

9. Olcott CW, Scott RD. Femoral component rotation during total knee arthroplasty. Clin Orthop Relat Res. 1999;367

10. Hanada H, Whiteside LA, Steiger J, et al. Bone landmarks are more reliable than tensioned gaps in TKA component alignment. Clin Orthop. 2007;462:137-42.

11. Chon JG, Sun DH, Jung JY, Kim TI, Jang SW. Rotational alignment of femoral component for minimal medial collateral ligament release in total knee arthroplasty. Knee Surg Relat Res. 2011 Sep;23(3):153-8. doi: 10.5792/ksrr.2011.23.3.153. Epub 2011 Sep 26.

12. Yoshii I1, Whiteside LA, White SE, Milliano MT. Influence of prosthetic joint line position on knee kinematics and patellar position. J Arthroplasty. 1991 Jun;6(2):169-77.

13. Hommel H1, Perka C2. Gap-balancing technique combined with patient-specific instrumentation in TKA. Arch Orthop Trauma Surg. 2015 Nov;135(11):1603-8. doi: 10.1007/s00402-015-2315-6. Epub 2015 Aug 28.

14. Laskin RS. Flexion space configuration in total knee arthroplasty. J Arthroplasty. 1995;10:657-60.

15. Whiteside LA, Arima J. The anteroposterior axis for femoral rotational alignment in valgus total knee arthroplasty. Clin Orthop Relat Res. 1995;321:168-72.

16. Franceschini V1, Nodzo SR1, Gonzalez Della Valle A1. Femoral Component Rotation in Total Knee Arthroplasty: A Comparison Between Transepicondylar Axis and Posterior Condylar Line Referencing. J Arthroplasty. 2016 Dec;31(12):2917-2921. doi: 10.1016/j.arth.2016.05.032. Epub 2016 May 27.

17. Victor J1. Rotational alignment of the distal femur: a literature review. Orthop Traumatol Surg Res. 2009 Sep;95(5):365-72. doi: 10.1016/j.otsr.2009.04.011. Epub 2009 Jul 9.

18. Berger RA, Crossett LS, Jacobs JJ, et al. Malrotation causing patellofemoral complications after total knee arthroplasty. Clin Orthop. 1998;356:144-53.

19. Yoshioka Y, Siu D, Cooke TD.The anatomy and functional axes of the femur. J Bone Joint Surg. 1987;69:873-80.

20. Park A, Duncan ST, Nunley RM, Keeney JA, Barrack RL, Nam D. Relationship of the posterior femoral axis of the "kinematically

aligned" total knee arthroplasty to the posterior condylar, transepicondylar, and anteroposterior femoral axes. Knee. 2014 Dec;21(6):1120-3. doi: 10.1016/j.knee.2014.07.025. Epub 2014 Jul 25.

21. Whiteside LA, Kasselt MR, Haynes DW. Varus-valgus and rotational stability in rotationally unconstrained total knee arthroplasty. Clin Orthop Relat Res. 1987.219: 147-57

22. Nedopil AJ, Howell SM, Hull ML. Does Malrotation of the Tibial and Femoral Components Compromise Function in Kinematically Aligned Total Knee Arthroplasty? Orthop Clin North Am. 2016 Jan;47(1):41-50. doi: 10.1016/j.ocl.2015.08.006.

23. Panni AS, Ascione F, Rossini M, Braile A, Corona K, Vasso M, Hirschmann MT. Tibial internal rotation negatively affects clinical outcomes in total knee arthroplasty: a systematic review. Knee Surg Sports Traumatol Arthrosc. 2018 Jun;26(6):1636-1644. doi: 10.1007/s00167-017-4823-0. Epub 2017 Dec 15.

24. Eckhoff DG, Piatt BE, Gnadinger CA, et al. Assessing rotational alignment in total knee arthroplasty. Clin Orthop. 1995;318:176.

25. Martin S, Saurez A, Ismaily S, Ashfaq K, Noble P, Incavo SJ. Maximizing tibial coverage is detrimental to proper rotational alignment. Clin Orthop Relat Res. 2014 Jan;472(1):121-5. doi: 10.1007/s11999-013-3047-y.

26. Passeron D, Gaudot F, Boisrenoult P, et al. Does lateral versus medial exposure influence total knee tibial compo nent final external rotation? A CT based study. Orthop Traumatol Surg Res. 2009;95:420-4.

27. Collins DJ1, Khatib YH2, Parker DA3, Jenkin DE4, Molnar RB5. Tibial rotation kinematics subsequent to knee arthroplasty. J Orthop. 2015 Jan 30;12(1):7-10. doi: 10.1016/j.jor.2015.01.012. eCollection 2015 Mar.

28. Stiehl JB, Dennis DA, Komistek RD, et al. In vivo determination of condylar lift-off and screw-home in a mobile- bearing total knee arthroplasty. J Arthroplasty. 1999,14 293

29. Miyanishi K, Nagamine R, Murayama S, et al. Tibial tubercle malposition in patellar joint instability: A computed tomography study in full extension and at 30 degree flexion. Acta Orthop Scand. 2000;71:286-91

30. Akagi M, Mori S, Nishimura S, et al. Variability of extraarticular tibial rotation references for total knee arthroplasty. Clin Orthop Relat Res. 2005;436:172-6.

31. Lutzner et al. Rotational alignment of the tibial component in total knee arthroplasty is better at the medial third of tibial tuberosity than at the medial border. BMC Musculoskeletal Disorders. 2010. 11:57

32. Incavo SJ, Coughlin KM, Pappas C, et al Anatomic rotational relationships of the proximal tibia, distal femur and patella: implications for rotational alignment in total knee arthroplasty. J Arthroplasty. 2003;18:643-8.


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Article received on February 19, 2019 and accepted for publishing on March 23, 2019.

ORIGINAL ARTICLES

The risk of bioterrorist and biocrime attack in the contemporary world

Ioana A. Gal1, Teodora B. Eremia1, Mihail S. Tudosie1,2, Viorel Ordeanu1,3,4

Abstract: The biological attack is the artificial spread by various means of pathogens that can cause serious infectious and contagious diseases as well as the spread of germ toxins that can be used by an aggressor as a means of fighting in order to reduce the troops’ fighting force, by causing serious disease outbreaks or by killing people, animals and/or plants.

Biological agents are microorganisms and/or microbial, animal or plant toxins, used as specific ammunition for biological weapons or used by terrorists in "bio-chem" attacks.

The risks of bioterrorism and biocrime attack in the contemporary world are real, and the history of the 20th century and the beginning of the 21st century confirms this.

It is necessary for preventive measures to be implemented on the unlawful use of biological agents. Early medical and non-medical countermeasures must be prepared for the prophylaxis, treatment and cessation of the consequences of any biological attack.

Keywords: biological attack, bioterrorism, biocrime, medical protection

INTRODUCTION

The biological attack is the artificial spread by various means

of pathogens that can cause serious infectious and

contagious diseases as well as the spread of germ toxins that

can be used by an aggressor as a means of fighting in order

to reduce the troops’ fighting force, by causing serious

disease outbreaks or by killing people, animals and/or plants.

Biological agents are microorganisms and/or microbial,

animal or plant toxins, used as specific ammunition for

biological weapons or used by terrorists in "bio-chem"

attacks.

Terrorism, according to the League of Nations (1937), can be

defined as the totality of criminal acts directed against a

state or made or planned in order to create a state of terror

in the minds of certain individuals, a group of people or the

general public.

The objectives of terrorism can be grouped as follows:

a) Achieving political goals.

b) Attracting the attention of domestic and international

public opinion to the "noble goal" pursued.

c) Undermining the authority of political regimes in some

countries by creating a state of inner strain, insecurity and

uncertainty, economic and social chaos.

d) Forcing authorities to meet certain requests.

g) Revenge on some officials.

h) Achieving military goals: management disruption at a

strategic or operational level, diminishing or partially

destroying the opponent's military potential, the disruption

of the logistics system, paralyzing communications and

telecommunication systems.

1 The Military-Medical Institute, Bucharest, Romania 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 Military Medical Research Center, Bucharest, Romania 4 “Titu Maiorescu” University, Bucharest, Romania

22

i) Religious fanaticism.

Bioterrorism consists in using or threatening to use the

weapon of mass destruction for claims, with the declared

intent of affecting the public health and/or the environment.

Currently, the following means are known for dispersing

biological agents:

- Using saboteurs;

- Using vectors of microorganisms such as insects, mites,

rodents or other infected animals;

- Incorporation of biological agents into explosive ammuni-

tion;

- Aerosolization – through aerosols released from the

ground, air or sea – is considered the most effective means

of contaminating large areas of territory within the shortest

feasible time interval.

With regard to the production of biological weapons, both

ordinary and resistant biological agents can be used, the

latter being preferred, because they cause a form of the

disease that can not be treated with the usual drugs, causing

a disease outbreak of greater magnitude and severity.

In general, biological attacks are masked by natural

epidemics, epizooties and epiphytosis, the latter two being

generally considered to be economic attacks, with the aim of

decreasing trade, implicitly, causing the decline of the

standard of living in the affected area.

Biological attacks can also be manifested in the form of

zooanthroponoses, affecting both animals and humans alike.

[1, 2].

BRIEF HISTORY

"Read the history and, thus, discover what will be" Nicolae

Iorga rightly said. The first "chemical weapons" - "toxic

smoke" were used around 424 BC in the Peloponnesian War.

The first users of the "biological weapon" (around 400 BC)

can be considered the Scythians, who used arrows soaked in

decomposing bodies or mixed with manure. The Spartans

used to cast sieves of sulfur-moistened wood on sieged

fortresses. Greek, Persian, and Roman literatures describe

how dead animals were used for fountain-contaminate.

The Mongols, in the siege of the Kaffa fortress in Crimea,

during the war waged between 1346 and 1347, used the

corpses of those killed by the plague in order to infect or

create a breach among the fortress defenders.

In the fifteenth century, the Spanish infested the French

wine with blood from those infected with the pests. Also, at

that time, Pizzaro distributed to the Americans in South

America garments contaminated with smallpox. In the

sixteenth century, the same virus was used by the English to

impregnate the blankets distributed to the ameridian tribes

that helped the French. In the war against Sweden in 1710,

the Russian troops used the same method as the Tartar army

did 400 years prior – namely, the use of the corpses of those

killed by the plague.

Table 1. Cases of illicit activity with biological agents around the world, confirmed by the judicial system, 20th century (W.S. Carus)

No Objectives Category TOTAL

cases Comments

Terrorist Criminal Others/not specified

1 Killing 4 17 0 21

2 Terror 6 9 22 37

3 Extortion 0 13 3 16

4 Losses 0 5 0 5

5 Anti-animal or cultures 1 2 0 3

6 Mass murder 4 0 0 4

7 Revenge 0 3 0 3

8 Disability 2 0 0 2

9 Political 1 0 0 1 The fewest

10 Unknown 9 7 72 88 The most

TOTAL 27 56 97 180

Comments The

fewest The most


23

Table 2. The objectives of using biological agents in the 20th century (W. S. Carus) [α]

No Activity Category TOTAL

cases Comments


1 Acquisition and use 5 16 0 21

2 Acquisition (possession) 3 7 2 12

3 Interest (attempt) 6 4 0 10 The fewest

4 Threat or false attack 13 29 95 137 The most

TOTAL 27 56 97 180

Comments The

fewest The most

During the Vietnam War, Americans used defoliant,

desiccant and sterilizing herbicides. These substances did

not fall under the Geneva Protocol of 1925 nor in the

Convention on the Prohibition of Chemical Weapons. In the

1970s, ricin was used to assassinate Bulgarian dissidents

Gheorghe Markov and Vladimir Kostov.

In 1976, the mayors of several US cities were the recipients

of letters that were delivered in envelopes on which had

been used an adhesive impregnated with lethal germs.

In 1979, among people working in a military microbiology

unit, was recorded an epidemic of lung anthrax, resulting in

over 60 deaths.

In 1984, in the US, members of the Bhagwan Shree Rajneesh

sect have contaminated the food in Oregon restaurants with

Salmonella Tiphi, causing 750 cases of major disease

outbreaks.

In 1988, Iraq was spreading toxic and biological substances

in Halabja, causing victims among the civilian population,

predominantly children and women. Also in 1995, Iraq

admitted to having in its posession Bacillus anthracis,

botulinum toxin and aflatoxins, declaring to be ready to use

them. All this demonstrates that, although the Convention

on the Prohibition of Chemical Weapons was signed in 1972,

the biological weapons research continued.

Since the end of 1992, there have been many more complex

epidemics in the US, Milwaukee area, with wide-ranging

effects: 400,000 cases of crypto-sporidium outbreaks from

water consumption; in the spring of 1993, a respiratory

epidemic with unidentified causes; during the fall of 1994,

250,000 cases of salmonella food poisoning.

On October 5th, 2001, in the US, Florida area, after having

inhaled the anthrax bacillus, a tabloid’s editor passed away.

On October 20th, 2001, three letters containing anthrax

spores were delivered to Washington DC, USA, having been

received by Tom Daschle, a member of the Senate, and by

Tom Brokaw from NBC News, as well as by the newspaper

"The New York Post ". On November 2nd, 2001, a letter

containing anthrax spores was found in Karachi, Pakistan,

which was addressed to the newspaper "Daily Jang". In

Santiago, a similar postal mailing resulted in disease

outbreaks of thirteen people.

Figure 1. Frequency of the illicit use of biological agents in the

20th century, on decades (W. S. Carus) [α]

After September 11, 2001, the danger of massive terrorist

attacks on the population of any part of the world is no

longer just a working hypothesis. Chemical, biological or

nuclear terrorism is, at present, one of the most serious

threats to all states. Given the trend of interethnic and

religious violence, as well as the number of cases of human

rights violations in certain "high-risk" areas around the

globe, analysts have warned against accentuating the risk of

using these types of weapons in terrorist actions, underlining

the imperative nature of urgently establishing non-

proliferation measures.

Table 3. Type of biological agent used (W.S. Carus) [α]

1 Living agents 136 cases

2 Toxins 26 cases

3 Unknown 6 cases

TOTAL 168 cases

24

COUNTERMEASURES

Combating bioterrorist attacks involves, first of all, the

intervention of the secret services, the police and the judicial

system. Also, the intervention of the National Health System,

the National Defense System, local communities and non-

governmental organizations is crucial in the fight against

these attacks. These non-medical contermeasures have an

active, prophylactic role, preparing the population in the

event of an attack. [3, 4, 5]

Table 4. Dissemination technique (W. S. Carus) [α]

No Dissemination Category TOTAL

cases Comments


1 Aerosolization 2 0 0 2 The fewest

2 Injection/topic 6 10 0 16

3 Food 1 20 1 22

4 Water 4 0 2 6

5 Natural vectors 0 1 1 2 The fewest

6 Not specified 10 13 79 102 The most

7 Unknown 5 10 2 17

TOTAL 28 54 85 167

Comments The

fewest The most

The responsibility for coordinating actions in these situations

lies with the government of the country holding the EU

Presidency, with the government of the country under

attack and/or with the European Center for Infectious

Disease Control.

The specific capabilities of the Medical Department of the

Ministry of Defense are important for the medical protection

against weapons of mass destruction and, in particular, for

the fight against biological attacks. The Center for Military

Medical Scientific Research has a Laboratory of Anti-

infective Medical Protection and Epidemiological

Emergencies, which functions as a specialized medical

protection unit against biological weapons. It conducts

military medical scientific research to protect troops and the

civilian population against biological weapons and/or toxins,

for biological warfare, bioterrorist attacks, or biological

accidents.

Table 5. The mortality rate in the attack with biological agents

(W.S. Carus) [α]

Purpose Cases Deaths

1 Bioterrorism 751 0

2 Biocrime 130 10

TOTAL 881 10

Source: Carus W. S. „Bioterrorism and Biocrimes. The illicit use of biological agents since 1990”, Center for Counterproliferation Research, National

Defense University, Washington DC, 2001. [6]

If we make a retrospective of the 20th century, the most

warrior of all, it is noticed that the practical use of

weapons/biological agents was a reality. [6]

It is noted that in the last decade of the 20th century there

were more cases than in the rest of the century.

OBSERVATION

An important component in the fight against biological

attacks is represented by medical espionage, a constantly

updated data base of new agents and existing diseases, thus,

becoming the key to finding the most effective treatment.

With regard to the measures required for the imminence of

a biological attack, individual protection means are used

such as the gas mask - which is not 100% effective, but it

decreases the amount of inhaled substance, having a

protective role, because for most substances in order for

harmfull effects to hapen it is necessary for large quantities

to be inhaled.

Chemotherapics present much wider benefits in regards to

the protection against biological weapons, acting switftly,

having a broad spectrum and being easily administered in

large communities.

Also, a very impressive step after a biological attack is the

decontamination by appropriate physical and chemical

means for the equipment, rooms, clothes, water sources,


25

soil, etc. [7, 8, 9, 10]

CONCLUSIONS

The risks of bioterrorism and biocrime attacks in the

contemporary world are real, and the history of the 20th

century and the beginning of the 21st century confirms this.

It is necessary to implement preventive measures on the

unlawful use of biological agents. Early medical and non-

medical countermeasures must be prepared for the

prophylaxis, treatment and cessation of the consequences of

any biological attack.

References:

1. Ordeanu V., Andrieș A., Hîncu L., Microbiologie și protecție medicală contra armelor biologice, Editura Universitară „Carol Davila” București, 2008.

2. Păun, Ludovic, Bioterorismul şi armele biologice, Editura Amaltea, 2003;

3. *** S.R.I., Centrul de informare pentru Cultura de Securitate, Centrul de Cooperare Operativă Antiterorista, Inamicul invizibil. Bioterorismul și armele biologice în lume, www.sri.ro

4. Chiş, Ioan, Popa, Cristina, Terorismul contemporan –fenomen şi infracţiune, Editura A.N.I, Bucureşti, 2007

5. Tun-Comşa, Cristian, Consideraţii privind terorismul contemporan, www.actrus.ro

6. Carus W. S. „Bioterorism and Biocrimes. The illicit use of biological agents since 1990”, Center for Conterproliferation Research, National Defense University, Washington DC, 2001.

7. Ioana-Alexandra GAL, Teodora Bianca EREMIA, Mihail Silviu

TUDOSIE, Colonel (r.) Viorel ORDEANU „Riscul de atatc bioterorist și de biocrimă în lumea contemporană”, comunicare Conferința anuală SUUMC București, sept. 2018

8. Ionescu LE, Ordeanu V, Dogaru M, Necsulescu M, Popescu DM, Bicheru SM, Dumitrescu GV. „Research for the development of logistics planning information support in health protection against biological agents”, Romaniam Journal of Military Medicine, vol. 121, no. 1/2018, p. 36-39

9. Ordeanu V, Necsulescu M, Popescu DM, Ionescu LE, Bicheru SM, Dumitrescu GV., Corlan G. „The concept of operationalization of an integrated platform for scientific research and expertise of war end bioterrorism biological agents” Romaniam Journal of Military Medicine, vol. 120, no. 2/2018, p.9-15

10. Popescu DM, Necsulescu M, Popescu DM, Ionescu LE, Bicheru SM, Dumitrescu GV., Ordeanu V. „Capabilities for identification and confirmation of baterial biological agents” Romaniam Journal of Military Medicine, vol. 119, no. 3/2016, p. 5-9

26

Article received on December 4, 2018 and accepted for publishing on March 30, 2019.

ORIGINAL ARTICLES

The concept of biological warfare and real biological attacks

Teodora B. Eremia1, Ioana A. Gal1, Iulia M. Staicu1, Mihail S. Tudosie1,2, Viorel Ordeanu1,3,4

Abstract: In the current military-political context, with the Cold War having ended, we find ourselves in full anti-terror war, in which Romania is a direct participant, as a member of N.A.T.O. and the E.U., and the issue of biological warfare and bioterrorism is again highly topical but bearing other valences.

There is information that there are still laboratories and plants specializing in the research and manufacture of biological weapons. Most of the results of such research are not intended to be published; however, a number of research guidelines that testify to the trends in the improvement of biological weapons and their means of use can be deduced from the data published by researchers from several research institutes.

We believe that the threats posed by bioterrorism are real and that it is mandatory to be prepared at any time to prevent, combat and liquidate the consequences of "bio-chem" attacks, respectively the management of the consequences.

Keywords: biological attack, biological warfare, biological agents, international legislation, medical protection

INTRODUCTION

In the current military-political context, with the Cold War

having ended (1947-1990), we find ourselves in full anti-

terror war (since 2001), in which Romania is a direct

participant, as a member of NATO and the EU, and the issue

of biological warfare and bioterrorism is again highly topical

but bearing other valences.

DEFINITIONS

War is a short or lasting conflict (whether military or not,

declared or not), between two or more groups, social

categories or countries, aiming to achieve financial, ethnic,

territorial, economic and political interests.

The biological warfare is the artificial spread by various

means of pathogens that can cause serious infectious and

contagious diseases as well as the spread of germ toxins that

can be used by an aggressor as a means of fighting in order

to reduce the troops’ fighting force, by causing serious

disease outbreaks or by killing people, animals and/or plants.

Weapons of mass destruction (WMD) are those weapons,

which, used by the aggressor, cause extensive material

damage (destruction of buildings, constructions, machinery,

installations, means of transport, etc.) as well as a large

number of victims among employees and unprotected

animals.

Chemical, biological, radiological and nuclear defence (CBRN

defence) represents the protection measures taken during

times of war or terrorist attacks, in the event of a chemical,

biological or nuclear attack.

The biological weapon is a system of unconventional

weapons of mass destruction, whose ammunition carries

biological agents and contaminates the enemy in order to

cause disease outbreaks for the latter.

Biological agents are microorganisms and/or microbial,

1 The Military-Medical Institute, Bucharest, Romania 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 3 Military Medical Research Center, Bucharest, Romania 4 “Titu Maiorescu” University, Bucharest, Romania


27

animal or plant toxins, used as specific ammunition for

biological weapons or used by terrorists in "bio-chem"

attacks.

Total war is a large-scale conflict in which policy makers

mobilize all available resources to ensure the destruction of

the rivals' ability to defend itself. During times of total war,

there are no actual non-combatants, meaning that all people

in a particular country - civilians and military alike – are

considered targets.

The hybrid war represents undeclared wars by those

participating states, where the military component is not

explicitly assumed and is by no means singular (they are

executed in concert as part of a flexible strategy with long-

term goals).

THE BIOLOGICAL ATTACK

Under the conditions of modern warfare, the effects of using

the biological weapon can be amplified by successive or

concurrent use with other WMDs. In a concrete battlefield,

the biological attack can occur with:

a) The enemy on the offensive – can use the biological

weapon to weaken the opponent's defence power. The most

likely objectives to be attacked with biological agents would

be:

1. Concentration of troops, resistance points

2. Reserve and support units

3. Air and sea troops found at bridge ends, traffic routes

clogs, operational reserves, etc.

In the tactical and operative space, pathogens of diseases of

short and virulent incubation, but non-transmissible from

human to human, will be used. Infected animals or insects

will not be used, as they would be dangerous for own troops.

In the strategic space, the aggressor will spread biological

agents that cause many types of diseases to disrupt the

battlefield, cause panic and aggravate material insurance.

b) The enemy on defence – could use the biological weapon

against opposing troop concentrations to reduce their force

of attack. Can be attacked with biological agents, the units in

the offensive, those in the second line or the back-ups, the

foreign military bases, etc.

In the operative space, infected insects and animals may also

be used to target troop concentrations; the passes, roads,

and crossing points may be contaminated to hinder the

pursuit.

Living organisms are the sole targets of these attacks, thus

buildings (for e.g.) being left intact, these being able to be

decontaminated and further used. The biological agent is

massively released into the area by the enemy and can

contaminate a large number of humans and/or animals

(anthroposoonosis) turning them into secondary sources of

infection by releasing in their turn pathogens in the external

environment. Except for those destined exclusively for

humans and for those common to both humans and animals,

there are also those biological agents destined exclusively

for the destruction of domestic animals and cultivated

plants.

THE PROVISIONS OF INTERNATIONAL LAW

From the point of view of International Law, biological

weapons are expressely prohibited because they fall under

the mass destruction weapons category, and their effect

cannot be limited in time and space, with medium-term

effects not always predictable. Moreover, the military use of

biological weapons is currently considered to be tactically

and operationally inefficient, being tactically difficult and

risky from a medical point of view, because an outbreak once

released can get out of hand.

Exceptions on using WMD

An important issue in controlling the Convention’s

implementation is the existence of certain exceptions

because the Convention cannot completely ban the use of

living agents and their toxins. So far, no convention banning

the use of a certain type of weapon against the enemy has

explicitly prohibited its use on its own population.

First of all, biological agents and some toxins can be used in

vaccine manufacturing, for diagnostic and treatment

purposes. For example, biological agents may be used in the

treatment of inflammatory bowel diseases such as Crohn's

disease inflammatory form with moderate or severe activity

that have not responded to conventional immune-

suppressive therapy or where immunosuppressant therapy

is contraindicated. They may also be used in patients with

moderate/severe RCUH who have not responded to

corticosteroid and immunosuppressive therapy or severe/

fulminant colitis. These patients are required to undergo

treatment with drugs such as Infliximab or Adalimumab

containing a chimeric anti-TNFα agent consisting of IgG1

monoclonal antibodies, 25% murine and 75% human,

respectively a fully humanized anti-TNFα agent, IgG1 type.

At the same time, the emergence of vaccines has greatly

revolutionized medical science since they carry an important

prophylactic role.

The vaccine is a biological product containing suspensions

(antigens) of attenuated, inactivated (killed) viruses or living

bacteria, or fractions thereof, which are administered in

28

order to induce a specific immune response. Depending on

the type of vaccine, fragments of pathogen agents were used

differently:

1. Viral vaccines – corpuscular vaccines with living

attenuated viruses (oral polio vaccine, rotavirus vaccine,

measles, rubella, varicella, amaryllis) or inactivated viruses

(inactivated polio vaccine, rabies, Hep A) and antigenic

fragments or viral subunits (Hep B, influenza vaccine)

2. Bacterial-corpuscular vaccines with living attenua-ted

germs (BCG) or killed (germs), (cholera vaccine, pertussis),

polysaccharide subunits (meningococcal, pneumococcal,

Hib, typhoid vaccine) or purified (pertussis acelular)

3. Anatoxin – diphtheria, tetanus

Thus, the BTWC allows all signatory countries to possess and

use reasonably small (grams) quantities of BWA for

defensive scientific research to obtain new means of

diagnosis, prophylaxis and treatment. But a real problem is

that these living biological agents can be multiplied on

demand and in any quantity or can synthesize toxins as

specific ammunition for biological weapons.

Secondly, one of the BTWC articles states that in case of

force majeure, when a state itself is threatened, it may notify

the UN three months before resuming the production of

biological weapons to deter the enemy. This also explains

why Israel, "an island in a sea of hostile Arabs", has not

signed and ratified the convention.

And Romania, which joined since 1972, ratified it only in

1979, in order to have an extra advantage in the face of a

possible assault of the USSR in the context after 1968. It

should be underlined that in fact Romania has not

researched, manufactured, stored, and has never used

biological or toxin weapons, nor did it have such an

intention, but it was indeed, the target of covert biological

attacks in the 20th century and, we must continue to take

preventive measures.

In this complex situation, effective legal measures for the

application of the BTWC need to be implemented

worldwide, but concrete actions are difficult to apply in

practice. The UN is in a position, as an international forum,

to impose and control compliance with the Convention,

being helped by the Security Council, the World Health

Organization as a specialized body.

STANAG are NATO standards for different areas that set

technical or operational standards in certain situations,

including in the field of biological warfare, and which need

to be adapted and implemented by Allied countries for

interoperability.

PREVENTION OF BIOTERRORISM ATTACKS

Preventing bioterrorist attacks is mainly a political and social

problem, which is primarily achieved through the

intervention of the secret services, police and the justice

system. Combating bioterrorist attacks also involves the

intervention of the National Health System, the National

Defence System, etc. The specific capacities of the Medical

Department of the Ministry of Defence are important for the

medical protection against the weapons of mass destruction

and especially for fighting against biological attacks,

permanently having the forces and means necessary for the

medical protection against the C.B.R.N agents.

The Center for Military Medicine Scientific Research

(CCSMM) has a Laboratory of Anti-infective Medical

Protection and Epidemiological Emergencies, which

functions as a specialized medical protection unit against

biological weapons. It conducts military medical scientific

research to protect troops and the civilian population

against biological weapons and/or toxins, for biological

warfare events, bioterrorist attacks, or biological accidents

targeting primarily: bacteria, viruses, fungi, etc. and their

toxins, to establish medical protection procedures, through

cooperation between different medical specialties:

microbiology, epidemiology, etc.

A first stage subsequent to the occurrence of a biological

attack is the identification of the causal agent, being

performed solely in a microbiology laboratory, starting from

correctly harvested samples (from the air, soil, water,

pathological products from the sick, etc.). The identification

operation must be quick and specific.

In the event of an immediate biological attack, the problem

at hand is the immediate decontamination by appropriate

physical and chemical means of the staff’s equipment, of the

rooms, the water sources and the food, etc. The appropriate

anti-epidemic measures to limit the spread of the infection

are, along with the above, another important stage in the

post-attack protocol, in which we will: isolate the sick and

the suspects, take care of individual and collective hygiene,

qarantine the D.D.D. actions and so on. If the agent has been

identified, we can perform emergency immunoprophylaxis

by using vaccines, by administering prophylactic or

therapeutic antibiotics, etc.

The protection against biological attacks depends on the

moment when the attack is detected, thus, when the media

shall signal the imminence of an attack, the possibility to

benefit from individual protection (ex-gas mask) and

collective protective means (shelters) should be available.

The biological means of protection and the emergency

prophylaxis with appropriate substances (serums, vaccines,


29

etc.) can be of good efficacy. Immunostimulators and

chemo-therapeutic agents (wide-spectrum antimicrobials)

can also be associated with these.

THE BIOLOGICAL WARFARE – A HISTORICAL REVIEW

There are very few data from the Prehistory and Antiquity

that testify to the use of biological weapons during warfare.

However, the latest research attests to the fact that the

Hittites were the pioneers of bioterrorism. The Hittite people

lived on a territory that today belongs mostly to Turkey.

Three thousand years ago, they used infected sheep aiming

at conquering enemy people. According to the study

performed by the Italian microbiologist Siro Trevisanato, the

bacterium considered the first weapon of mass destruction

in history was Francisella Tularensis, responsible for

tularemia, an infectious and contagious rodent disease,

caused by a bacterium and transmitted to domestic animals

and humans, manifesting itself by fever, chills, vomiting, etc.

The disease still exists nowadays and, if not treated properly,

can lead to death. Studying ancient papers, researchers have

proven that tularemia first appeared in a Phoenician city

(located on the border between Lebanon and Syria today) in

the Middle East in the 14th century BC. The Hittites

plundered this city in 1325, bringing with them infected

animals, which may have spread the disease – also referred

to as the "Hittite Plague" - throughout its territory, as

explained by the researcher. Trevisanato points out that

there are several papers attesting the epidemic. At the time

of tularemia’s utter virulence, the Hittites came to the

attention of a neighboring population of the city of Arzawa

(Western Anatolia), who took advantage of their weakness

to invade their territory.

During the Middle Age as a Mongol saw his comrades die of

plague in the three years of the siege of Caffa's Black Sea city,

founded by the Genovese, he had the brilliant idea of

throwing corpses over the city walls. The Genoese left the

city, but the plague spread across Europe.

In the Modern Age – the First World War brought a more

sophisticated biological warfare, with the development of

microbiology, many pathogens causing diseases could be

identified that could then be cultivated in the laboratory.

There are suspicions about the use of plague against Russian

troops at St. Petersburg. Petersburg in 1915, about horses

being infected in US ports for British and French armies.

In the Contemporary Age – extraordinary intelligence has

been invested in the development and modernization of all

categories of weapons. Each country classified biological

programs at the highest level of secrecy; there is little

evidence today about the details of the programs being

carried out, with only little evidence on the existence of such

programs in the current media. Specific anti-human, anti-

animal and anti-plant programs have been developed,

agents have been standardized for use as weapons, and

insects have been studied for use as natural dispersion

vectors.

PERSPECTIVES

The range of pathogens used as biological weapons is very

wide, which gives rise to particular difficulties in the

elaboration of the protection and treatment measures.

Types of agents:

1. Bacteria: anthrax, plague, cholera etc;

2. Viruses: yellow fever, tick-borne encephalitis (TBE),

smallpox, etc;

3. Rickettsia: Q fever, exanthema of typhus etc;

4. Pathogenic fungi: coccidioidoreo etiological agents, etc;

5. Toxins: bacterial (Botulinum, staphylococcal, etc.), fungal,

of animals or plants (ricinotoxin).

These are only the pathogens found in nature. But new

genetic techniques now allow us to obtain germs with new

qualities, not naturally occurring (modified or hybridized)

and which can be considered more dangerous by their

pathogenic effect and increased resistance in the external

environment.

Some agents have a lethal effect, while others have an

incapacitating effect, leaving man out for a period of time

ranging from a few hours to a few weeks.

They can be joined by immunosuppressive substances,

which disrupt the mechanisms of the body's anti-infectious

resistance, exposing it to current infections or to those

deliberately disseminated.

In the case of a biological attack, it should be stressed that

the possibility of using two or more biological agents

simultaneously, whose effects combine or potentiate, or can

be used with other weapons of mass destruction, is

estimated.

We can also mention the existence of biological agents

destined exclusively for destroying domestic animals and

cultivated plants (e.g. avian influenza, barberry rust for

plants) that can lead to large losses or can be used to destroy

the economy of a competing country etc.

CONCLUSIONS

There is information that there are still laboratories and

plants specializing in the research and manufacture of

biological weapons. Most of the results of such research are

not intended to be published; however, a number of

30

research guidelines that testify to the trends in the

improvement of biological weapons and their means of use

can be deduced from the data published by researchers from

several research institutes (e.g. the study of some of the

most dangerous communicable diseases in humans and

animals that currently have a very narrow spreading area).

Another evidence of concern in the field of biological

weapons is that the military personnel of some states are

regularly exposed to prophylactic vaccines against some

infectious diseases that are not circulating in the respective

country.

We believe that the threats posed by bioterrorism are real

and that it is mandatory to be prepared at any time to

prevent, combat and liquidate the consequences of "bio-

chem" attacks, respectively the management of the

consequences.

References:

1. Mihail-Silviu Tudosie, Teodora Bianca Eremia, Ioana Alexandra Gal, Iulia Madalina Staicu, Viorel Ordeanu - Conceptul de razboi biologic si atacurile biologice reale, Comunicare Conferinţa Anuală a Spitalului Universitar de Urgenţă Militar Central “Dr. Carol Davila” Bucuresti 10-13 octombrie 2018

2. Ordeanu V. et all. Microbiologie si protectie medicala contra armelor biologice, Editura Universitara Carol Davila, Bucuresti, 2008

3. https://en.wikipedia.org/wiki/CBRN_defense

4. https://ro.wikipedia.org/wiki/R%C4%83zboi_biologic

5. http://www.ccpb.ro/despre-bioterorism/scurt-istoric-al-armei-si-razboiului-biologic

6. „Convenţia privind interzicerea perfecţionării, producţiei şi stocării armelor bacteriologice (biologice) şi cu toxine şi la distrugerea lor (BTWC)” http://www.ancex.ro/? pag=69

7. Convenţia pentru Arme Biologice, http://www.ccpb.ro/ despre-bioterorism/conventia-pentru-arme-biologice


31

Article received on April 15, 2019 and accepted for publishing on June 3, 2019.

ORIGINAL ARTICLES

Morphological characteristics of the celiac-mesenteric trunk

P. Bordei1, R. Baz1, V. Rusali1, Cristian R. Jecan2,3, V. Ardeleanu1,4,5,6

Abstract: The present paper describes the morphological characteristics of 12 celiac-mesenteric trunk cases highlighted by angiography-computed tomography (CT), characteristics met only in male cases (1.82% of the cases). In relation to the vertebral column, the origin of the trunk was found in the the upper half of the L1 vertebra – intervertebral disk between L1 and L2 vertebrae. At the level of its origin from the aorta, the celiac-mesenteric trunk had an external diameter with values ranging from 8.7-13.4 mm, the aortic ostium of the celiac-mesenteric had a vertical diameter ranging from 8.8 to 13.1mm, the horizontal diameter values ranging from 8.8 to 11.2mm. At the level of its origin, the celiac-mesenteric trunk and the aortic wall had an angle with values ranging from 30.0o to 90.2o. The length of the celiac-mesenteric trunk had values ranging from 21.8 to 42.5 mm, most frequently met values were ranging from 30.7 to 33.5mm. At the level of its bifurcation, the celiac-mesenteric trunk had an angle with values ranging from 82.2 to 120,7, most frequently met values were over 90o. The celiac trunk resulted from the celiac-mesenteric bifurcation had an exterior diameter of 6.2 – 10.2 mm, values that in relation to exterior diameter the celiac-mesenteric originated, it represented 65.57 – 92.47% of its external diameter. The celiac trunk up to the end of its ramification had a length with values ranging from 6.3 to 16.8 mm. In all cases being a hepatosplenic trunk, the left gastric aorta originated in the abdominal aorta in 10 cases (83,3% of the cases) and in the other 2 cases, the left gastric aorta originated in one case under the end bifurcation of the celiac trunk whereas the other case in the celiac-mesenteric trunk, before its end bifurcation. The superior mesenteric artery resulting from the ramification of the celiac-mesenteric trunk had an external diameter with values ranging from 4.4 to 8.5 mm that represented 44.44 – 85.06% of the external diameter of the celiac-mesenteric trunk.

Keywords: celiac-mesenteric trunk – morphological characteristics

INTRODUCTION

The celiac trunk and the superior mesenteric aorta are

collateral branches of the abdominal aorta that are

originating independently from its trunk, assuring the

vascularization of the biggest part of the digestive tube and

its annexed glands as well as the vascularization of the

spleen. There have been cases where both arteries

originated from the aorta through a common trunk, the

celiac-mesenteric trunk, with frequencies of [1] and 3% [2, 3]

– most authors pointing a percentage between 1.0 and 2.5%

of the cases. According to [4], during the embryonal

development, out of the 4 roots of the omphalomesenteric

artery, roots 2 and 3 will disappear and the persistent root

will unite by longitudinal anastomosis resulting into left

gastric artery. The persistent root will give birth to the celiac

trunk and the other one will issue the superior mesenteric

artery. In the case where the first and the fourth root

disappear, then the celiac-mesenteric trunk will originate.

MATERIAL AND METHODS

The material for this study comprised of 16 angiography-

computed tomography (CT), performed with GE LightSpeed

VCT high image resolution 64-slice CT system and GE

LightSpeed 16- slice CT system, both systems within the

1 “Ovidius” University of Medicine and Pharmacy, Constanţa 2 ‘’Agripa Ionescu’’ Hospital, Bucharest 3 ‘’Carol Davila’’ University of Medicine and Pharmacy Bucharest 4 Arestetic Clinic Galati 5 ’’Dunarea de Jos’’ University from Galati 6 General Hospital CFR Galati

32

premises of the Clinical Emergency County Hospital “Sf.

Andrei” in Constanta. The above-mentioned 12 cases were

studied out of 2220 patients that presented for a specialist

consult for various medical reasons, during the period

between July 2012 and June 2016, in Dobrogea area of the

country, south - eastern part of Romania. From the total

number of patients, 830 were females (37.39%) and 1390

were males (62.61%). The study was conducted with respect

to the following parameters: the level of origin of the celiac-

mesenteric trunk from the aorta in relation to the vertebral

column, the trajectory and the angle formed from the origin

of the celiac-mesenteric trunk with the aortic wall, the

exterior diameter as well as the endovascular diameter of

the celiac-mesenteric trunk at the level of its aortic origin, its

length up to its bifurcation, the angle formed between its

two terminal branches as well as the diameter and the

trajectory.

RESULTS

In the present study, we met 12 cases with celiac-mesenteric

trunk (0.54% of the total cases), all male cases (0.86% of the

male cases). In relation to the vertebral column, the origin of

the trunk was located in the upper half of the L1 vertebra –

intervertebral disk between L1 and L2 vertebrae. In 7 cases

(58.33% of the cases) the origin was located at the level of

the upper half of the L1 vertebra, most frequently near the

upper margin of the vertebral body. In 3 cases (25% of the

cases), the celiac-mesenteric trunk originated in the lower

half of the L1 vertebra, whereas in 2 cases (16.67% of the

cases) it originated at the level of the intervertebral disk L1

– L2.

The celiac- mesenteric trunks originating from the aorta was

located higher than the origin of the renal arteries, at a

distance of 8.9 – 20 mm from the right renal artery,

respectively 9.2 – 22.8 mm from the left renal artery. This

indicates that the right renal artery originates most

frequently from the aorta than the left renal artery.

The celiac-mesenteric trunk originating from the aorta had

an external diameter with values ranging between 8.7 to

13.4 mm, in 8 cases (66.67% of the cases) with a diameter

ranging between 11.4 and 13.4 mm. By comparing the

external diameter of the celiac-mesenteric trunk with the

external diameter of the abdominal aorta at the level of its

origin, we have discovered differences in values, ranging

from 9.3 to 13.8 mm between the two diameters,

representing 40.09 – 58.01% of the external aortic diameter.

The aortic ostium of the celiac-mesenteric trunk had a

vertical diameter with values ranging from 8.8 to 13.1 mm –

the horizontal diameter ranged between 8.4 to 11.2 mm. In

all cases the aortic ostium had an oval shape. In 8 cases

(66.67% of the cases) the long axis was horizontal and in 4

cases (33.33% of the cases), the axis was vertical. By

comparing the vertical diameter of the aorta, the ostium

trunk had a vertical diameter with values ranging between

34.92 to 55.26% of the aortic one, whereas in the case of the

horizontal diameter it presented with values ranging

between 41.79 to 54.37% of the horizontal aortic diameter.

At the level of its origin, the celiac-mesenteric trunk created

and angle with the aortin wall, with values ranging between

30○ to 90.2○ – extreme values had been found in one for each

value, most frequent value for the angle being of 60○. This

explains the trajectory of the celiac-mesenteric trunk, most

frequently position being transverse anterolateral to the

right, an aspect met in 10 cases (83.33% of the cases) and

only 2 cases having a horizontal trajectory (transversal)

presenting with an angle of 90,2○ respectively 90,3○.

The length of the celiac-mesenteric trunk had values ranging

between 21.8 to 42.5 mm, most frequently met values

ranging from 30.7 to 33.5 mm.

The bifurcation of the celiac-mesenteric trunk into the two

arteries had an angle with values ranging from 82.2○ to

120.7○, most frequently met values being over 90○ (83.33%

of the cases). In the case that, after the bifurcation, the

superior mesenteric artery had a transverse anterolateral to

the right trajectory, the celiac trunk would always be

ascending to the right, sometimes close to a vertical position.

The celiac trunk resulting from the celiac-mesenteric

bifurcation had an external diameter with values ranging

from 6.2 to 10.2 mm, extreme values have been met in only

one case for each value; the rest of the cases with values

ranging between 8.0 to 9.2 mm. In relation to the external

diameter of the celiac-mesenteric trunk from which it

originated, the celiac trunk had an external diameter with

smaller values by 0.7 to 4.2 mm, representing 65.57 –

92.47% of its external diameter.

The length of the celiac trunk up to its ending ramification

had values ranging between 6.3 to 16.8 mm – extreme

measures were found in only one for each case. All cases

presented with a hepatosplenic trunk with the left gastric

artery originating from the abdominal aorta in 10 cases

(83.33% of the cases), at a distance of 15.1 – 18 mm above

the origin of the celiac-mesenteric trunk. In one case, the left

gastric aorta originated from the terminal bifurcation of the

celiac trunk whereas in the other case it originated from the

celiac-mesenteric trunk before its ending ramification.

The endovascular ostium of the celiac trunk had a vertical

diameter with values ranging from 7.1 to 8.6 mm, with a


33

horizontal diameter of 6.6 to 8.6 mm. In 11 cases (91.67% of

the cases) the horizontal diameter was bigger than the

vertical diameter by 0.5 – 1.3 mm, thus having an oval-

shaped horizontal long axis. In only one case (8.33% of the

cases) the diameter of the ostium was bigger vertically than

horizontally, with a difference of 0.5 mm thus having an oval

shape with a vertical long axis.

The superior mesenteric artery resulted by the ramification

of the celiac-mesenteric trunk had an external diameter with

values ranging between 4.4 to 8.5 mm, smaller by 1.3 – 5.9

mm, representing 44.44 – 85.06% of the external diameter

of the celiac-mesenteric trunk.

Table: Percentage frequency of the celiac-mesenteric trunk

Author CMT frequency Differences

Adachi 2.4 % - 1.86 %

Babu 2.79 % - 2.25 %

Chen 0.7 % - 0.16 %

Eaton 0.54 % 0

Ferrari 1.7 % - 1.16 %

Jones 1.7 % - 1.16 %

Kornafel 1.5 % - 0.96 %

Lippert 3 % - 2.46 %

Lipshutz 2.4 % - 1.86 %

Matusz 0.68 % - 0.14 %

Michels 2.5 % - 1.96 %

Mu CG 0.98 % - 0.44 %

Natsume 0.60 % - 0.06 %

Nelson 2.0 % - 1.46 %

Panagouli 0.76 % - 0.22 %

Piquand 2.0 % - 1.46 %

Rio Branco 3.0 % - 2.46 %

Song 1.06 % - 0.52 %

Yadov 2.5 % - 1.96 %

Our study 0.54 % of the total cases

0.86 % male cases

The endovascular ostium of the superior mesenteric artery

had a vertical diameter with values ranging from 6.8 to 8.5

mm, with a horizontal diameter of 6.2 to 8.5 mm. In 11 cases

(91.67% of the cases) the horizontal diameter was bigger

than the vertical diameter by 0.3 – 1.1 mm, having an oval

shape with a horizontal long axis. In only one case (8.33% of

the cases) the diameters of the ostium were equal, thus

having a round shape.

By comparing the external diameters of the celiac trunk and

the superior mesenteric aorta, we have discovered that in 11

cases, the superior mesenteric aorta had a smaller diameter

than the celiac trunk, representing 47.83 – 83.33% of the

diameter of the celiac trunk and only in one case the

diameter of the celiac trunk was smaller than the one of the

superior mesenteric artery, representing 83.73% of its

diameter.

DISCUSSIONS

Analyzing the results, we had and comparing them to the

data in the existing literature referring to the morphological

characteristics of the celiac-mesenteric trunk, we have

discovered there is no thorough description of these, most

authors mentioning only the frequency as a vascular

variation.

By comparing the results of the study with the data existing

in the literature we had the possibility to consult, we

discovered that our results were the same with the results

of [1], whereas in the rest of the cases we found differences

with values ranging from 0.06 to 2.46%. Compared with the

statistics of [5, 6, 7, 8, 9, 10] our results were smaller with

values ranging between 0.06% [5] and 0.52% [10]. Compared

with [11] the results we had were smaller by 0.96% and

values ranging from 1 to 2.25% we most frequently met

[Adachi, cited by 8, 12, 13, 14, 15, 16, 17, 18, 19]. Babu [19]

is the only author mentioning the frequency of the celiac-

mesenteric trunk in both genders – our results on male cases

being smaller by 0.46%. Unlike our study where the presence

of the celiac-mesenteric trunk was met only in male cases,

Babu [19] discovers the presence of celiac-mesenteric trunk

having a wider spread within female cases (1.47% of the

cases). In relation to the statistics of [2, 3], the results are

lower, the difference being by 2.46%. Lippert [3] discovers

the presence of the gastro-hepato-spleno-mesenteric trunk

in 2% of the cases, a difference of 1.95% from our study, and

the hepato-spleno-mesenteric trunk with the origin of the

left gastric aorta from the aorta in 1% of the cases, a

difference of 0.55% from our study. Babu [19] finds that in 3

cases (15.79% of the met celiac-mesenteric trunks), the

origin of the left gastric aorta was in the celiac trunk resulted

from the celiac-mesenteric bifurcation at the level of the

abdominal aorta. In a case described by Anupama [20], from

the celiac trunk resulted the hepatic artery, the splenic

artery, the left gastric artery and a branch that participated

in formation of the gastro-duodenal artery. In the specialist

literature, we have not met celiac-mesenteric trunk cases

where the left gastric artery originated anteriorly to the

ending ramification of the celiac-mesenteric trunk, closer to

its origin.

34

The length of the celiac-mesenteric trunk given by Anupama

[20] is of 13.00 mm, Tugrul [21] specifics a length of 13.42

mm, both values being smaller than the ones we found in

our study by 8.80mm, respectively 8.38 mm smaller than the

minimum length and 29.5 mm, respectively 29.08 mm

smaller than the length we have measured in our study.

With regards to the diameter of the celiac-mesenteric trunk,

Tugrul [21] finds an external diameter of 13.98 mm, a

diameter bigger by 0.58 mm than what we have measured

for the maximum value and with 5.28mm bugger than the

minimum diameter. Compared to our results Tugrul [21]

finds the celiac trunk resulting from the celiac-mesenteric

bifurcation with a diameter (7.09 mm) bigger by 0.89 mm

from the minimum diameter and smaller by 3.11 mm from

the maximum value of the diameter we have measured. At

the level of the superior mesenteric artery Tugrul [21] finds

a diameter of 5.25 mm, bigger by 0.86 mm from the

minimum diameter and smaller by 3.25 mm than the values

of the maximum diameter we have measured in the study.

Hemanth [22] finds an external diameter of 8.7 mm for the

superior mesenteric artery, bigger by 4.3 mm than the

minimum diameter, respectively by 0.2mm than the

maximum value within our study.

CONCLUSION

There is a relatively low frequency of celiac-mesenteric trunk

cases described in the literature, our case having the lowest

frequency. The differences between different authors is

related to the number of cases they have studied and due to

the fact that cases where the hepatic artery was the only one

originating from the trunk weren’t taken into consideration

as well as the methods used for the research. There is a

difference between the classical methods (dissections,

intramuscular injections) in relation to the modern methods,

especially MDCD that has better results than the

conventional angiography [17, 23]. With modern exploration

methods, it has been noted that a greater number of

vascular variants and malformations have been observed

than those reported in the specialist literature involving

other methods. We could add as a cause to the differences

and the probable existence of some peculiarities related to

the geographical area, which exist between authors who

carried out their research on different meridians of the

world.

We consider the name of vascular malformation used by

some authors when talking about the celiac trunk is not the

correct name, whereas vascular variant seems a more

appropriate name since all vascular branches of the two

arteries are present, having the same morphological

characteristics as in the case where they originated

independently from the aorta, also because they don’t affect

the vascular territories they serve.

The present study is interesting not only for a morphologist

but also, knowing the different types of anatomical variants

is fundamental for the planning of abdominal surgical

procedure and is important to the radiologist as well, as

specified by [10, 23].

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23. Iezzi R, Santoro M, Dattesi R, Pirro F, Nestola M, Spigonardo F, Cotroneo AR, Bonomo L (2012) Multi-detector CT angiographic imaging in the follow-up of patients after endovascular abdominal aortic aneurysm repair (EVAR). Insights into Imaging, 3(4): 313–321

24. *** Terminologia Anatomica. International Anatomical Terminology. Federativ Committee on Anatomical Terminology (1998) Ed. Thieme-Stuttgart, 75-77.

36


ORIGINAL ARTICLES

Local treatment options for management of loco-regional esophageal squamous cell carcinoma

Tülay Eren1, Gökşen İ. İmamoğlu1, Fatih Yildiz2, Süheyla A. Arslan3, Sultan A. Kocacan1, Salih Z. Çakar4, Ozan Yazici4, Doğan Yazılıtaş1, Nuriye Özdemir3, Berna Öksüzoğlu2

Abstract: Aim: Surgical treatment is the main treatment method for esophageal cancer. The prognosis is poor due to high local recurrence and distant metastasis rates. Study aims to evaluate the most effective local treatment modality esophageal squamous cell carcinoma (SCC) according to real life data.

Method: 136 patients were studied retrospectively. All patients were middle or lower esophageal cancer and had the SCC histology. Patients were divided into the surgical resection, definitive CRT (dCRT), and multimodal treatment groups according to curative local treatment they received.

Result: 32.4% were in the surgical, 36% were in the dCRT, and 31.6% were in the multimodal group. Median disease-free survival was 21 months (95% CI 14-27) in the surgical group, 8 months (95% CI 4-11) in the dCRT group, and 18 months (95% CI 0-39) in the multimodal group (p=0.059). The median overall survival was found to be 40 months (95% CI 0-92) in the surgical group, 19 months (95% CI 15-22) in the dCRT group, and 54 months (95% CI 11-96) in the multimodal group (p=0.012). In multimodal group, the number of patients receiving preoperative CRT was 25, and postoperative CRT was 18. Median OS was 47 months (95% CI 0-99) in the preoperative CRT group, and 64 months (NA) in the postoperative CRT group (p=0.302).

Conclusion: DFS and OS contributions of multimodal treatment in esophageal SCC have been shown in the present study. The addition of CRT to surgery in the preoperative or postoperative period has a contribution independently of the treatment sequence.

Keywords: multimodal treatment, surgery, definitive chemoradiotherapy, squamous cell, esophagus cancer

INTRODUCTION

Esophageal cancer is the seventh most common cause of

cancer-related deaths worldwide. In 2012, 455,800 people

were diagnosed with, and 400,200 people died from

esophageal cancer [1].

Surgical resection has traditionally been the primary

treatment for esophageal cancer in order to maintain local

disease control and prolong life expectancy. The median

survival is 15-18 months, and the 5-year survival rates are

20-25% after esophagectomy [2].

Failure in the treatment is generally due to recurrence and

metastases. Developments in standard therapy are ongoing.

Radiotherapy can provide locoregional control in esophageal

cancer, while chemotherapy has both local and systemic

antineoplastic effects. With the development of

multidisciplinary treatment approaches, the use of

1 Dışkapı Yıldırım Beyazıt Research and Education Hospital, Ankara, Turkey 2 Ankara Onkoloji Research and Education Hospital, Ankara, Turkey 3 Yıldırım Beyazıt University, Ankara, Turkey 4 Numune Research and Education Hospital, Ankara, Turkey

Corresponding author: Tülay Eren

[email protected]


37

chemoradiotherapy (CRT) in addition to surgery has become

the most frequently used treatment method [3].

In esophageal cancer treatment, the results obtained from

surgical treatment alone are not satisfactory in terms of

locoregional recurrence or distant metastasis rates. This has

paved the way for multimodal treatment approaches.

Together with the multimodal treatment,

chemoradiotherapy (CRT) added to surgery in the

preoperative or postoperative period, aims to provide

disease-free survival and an increase in life expectancy.

Preoperative chemoradiotherapy has begun to be used to

increase the R0 resection rates by reducing the tumor stage

before surgery, thereby contributing to survival [4-10]. The

application of surgery after preoperative

chemoradiotherapy is now a well understood and effective

treatment [11, 12]. In the ChemoRadiotherapy for

Oesophageal cancer followed by Surgery Study (CROSS), a

pilot study related to preoperative chemoradiotherapy, the

preoperative chemoradiotherapy was reported to increase

the median OS approximately 2-fold when compared to

surgical treatment alone (49.4 vs 24.0 months) [4].

In the literature, there are data about the postoperative

(adjuvant) activity of chemo-radiotherapy in addition to its

preoperative activity. In the past, the major problem in

applying chemoradiotherapy in the postoperative period

was the inability of patients to complete the scheduled

treatment due to poor performance of the patients after

surgery, but currently developing surgical and radiotherapy

techniques have partly removed this problem. Studies by

Rice et al. [13] and Bedard et al. [14] have demonstrated the

survival advantage of postoperative CRT. In the

retrospective study by Rice, the median survival was stated

to be 28 months with surgical postoperative CRT, and 15

months with surgery alone (p<0.05). In the study by Bedard,

the median overall survival was reported to be 47.5 months

with postoperative CRT and 14.1 months with surgery alone

(p=0.001) [14].

Following the studies showing the benefits of preoperative

and postoperative chemoradiotherapy, studies about

treatment sequence emerged. Current data on the

prognostic effect of local treatment sequence in esophageal

cancer remain controversial [15, 16]. In a study based on the

SEER data, it was determined that preoperative CRT ensured

better survival compared to postoperative CRT [15], while a

prospective study reported no difference in survival

between taking the CRT in the preoperative or postoperative

period [16].

In the light of this information, the prognostic implications

of optimal multimodal treatment, surgery and chemo-

radiotherapy sequence in the treatment of esophageal

cancer are still controversial. No standard guideline has been

created in this particular. The main aim of this study was to

evaluate the most effective local treatment modality in non-

metastatic, middle and lower esophageal squamous cell

carcinoma (SCC) according to real-life data.

METHODS

A total of 136 patients diagnosed between the years 2005-

2016 in 3 different oncology clinics were included in the

study. The patient data were reviewed retrospectively.

Patients aged 18-70 years, without distant metastasis,

treated for curative purposes, with ECOG performance

status 0-2, with appropriate liver/renal reserve, middle and

lower esophagus involvement, and with SCC histology were

included in the study. Patients with adenocarcinoma

histopathology, with cervical esophagus involvement, and

those who only received RT as a local treatment were not

included in the study.

All the patients were applied with thorax and entire

abdomen computed tomography (CT) or positron emission

tomography (PET-CT) or endoscopic ultrasonography (EUS)

examinations for the purpose of staging prior to local

treatment. The patients were divided into 2 groups as local

and local advanced disease according to the radiological

results at the time of diagnosis. Radiologically, patients with

T4 tumors or lymph node positivity were considered to have

locally advanced disease, while non-T4 patients with lymph

node-negativity were considered to have local disease.

The patients were divided into 3 groups as those who

underwent only surgical resection, only definitive CRT

(dCRT), and multimodal treatment (preoperative CRT or

postoperative CRT) according to the curative local treat-

ments they received and were evaluated comparatively.

Platinum-based combination therapies (fluorouracil or

taxane) were administered concomitantly with the chemo-

therapy regimen in patients receiving chemoradiotherapy.

In CRT planning, a 3 mm interslice distance CT scan was

performed on all patients in the supine position. In patients

undergoing definitive and preoperative chemoradiotherapy,

the gross tumor volume (GTV) was determined for primary

mass and involved lymph nodes using thoraco-abdominal

CT, PET-CT, endoscopy and EUS information, if available. The

clinical target volume (CTV) was established by giving a

margin of 4 cm in the superior-inferior direction and 1 cm in

the radial direction to the primary mass. The planning

volume was obtained by allowing 1 cm extra margin to this.

The spinal cord, lungs, and organs at risk, such as the heart,

remaining within the area were contoured. In postoperative

38

therapy, bilateral supraclavicular or celiac lymph nodes were

included in the area in the location of all mediastinum and

primary masses.

The gastroesophageal intersection and proximal stomach

were included in the area in distal localized tumors.

The radiotherapy (RT) plans were made by applying the 3-

dimensional conformal technique. Patients undergoing

definitive CRT (dCRT) received a total of 50.4 Gy

radiotherapy, and those undergoing pre-operative or

postoperative CRT received a total of 45 Gy radiotherapy,

which was applied as 1.8 Gy daily for 5 days a week.

All patient records were reviewed clinically, pathologically

and in terms of treatment characteristics. The long-term

survival data of patients were obtained from the patient files

and from the data of the Turkish civil registry office.

Approval for the study was granted by the Ethics committee

of Sağlık Bilimleri University Dışkapı Yıldırım Beyazıt Training

and Research Hospital.

The data were analyzed using SPSS 18.0 for Windows

software. Descriptive statistics were expressed as mean ±

standard deviation or median (minimum-maximum) for non-

continuous numerical variables, and as number (n) and

percentage (%) for categorical variables.

The progression and overall survival rates of all cases were

investigated using Kaplan-Meier survival analysis. The 2-year

and 3-year cumulative progression and overall survival rates

together with mean lifespan and 95% confidence intervals

for these terms were calculated. The demographic

characteristics of the patients were assessed using

descriptive statistical methods. Parameters that were

significant in univariate analysis were assessed using Cox

regression multivariate analysis. A value of p<0.05 was

accepted as statistically significant.

RESULTS

A total of 136 patients were evaluated comprising 32.4%

(n=44) in the surgical group, 36% (n=49) in the definitive CRT

(dCRT) group, and 31.6% (n=43) in the multimodal treatment

group. Of the total patients, 52.2% were female and 47.8%

were male.

The demographic characteristics of the patients are shown

in Table 1.

Table 1: Demographic characteristics of the patients

Surgery (n=44)

dCRT (n=49)

Multimodal Treatment

(n=43) p Value

Age (years) Median (min-max) 52 (32-76) 58 (25-77) 50 (32-70) 0.001

Gender Female 26 (59.1%) 21 (42.9%) 24 (55.8%)

0.249 Male 18 (40.9%) 28 (57.1%) 19 (44.2%)

Smoking Smokers 20 (45.5%) 26 (53.1%) 12 (39.5%)

0.426 Non-smokers 24 (54.5%) 23 (46.9%) 26 (60.5%)

Alcohol Use Users 15 (34.1%) 14 (28.6%) 19 (44.2%)

0.288 Non-users 29 (65.9%) 35 (71.4%) 24 (55.8%)

Comorbid disease Present 15 (34.1%) 16 (32.7%) 8 (18.6%)

0.208 Absent 29 (65.9%) 33 (67.3%) 35 (81.4%)

Cancer history in family

Present 9 (20.5%) 14 (28.6%) 9 (20.9%) 0.581

Absent 35 (79.5%) 35 (71.4%) 34 (79.1%)

Tumor Grade

Well 2 (4.5%) 5 (10.2%) 4 (9.3%)

0.240 Moderate 8 (18.2%) 6 (12.2%) 5 (11.6%)

Poor 3 (6.8%) 12 (24.5%) 4 (9.3%)

Location of tumor

Mid-esophagus 18 (40.9%) 25 (51.0%) 25 (58.1%) 0.271

Lower esophagus 26 (59.1%) 24 (49%) 18 (41.9%)

Pre-clinical stage Early 26 (59.1%) 11 (22.4%) 20 (46.5%)

0.001 Locally advanced 18 (40.9%) 38 (77.6%) 23 (53.5%)


39

When the postoperative stages of 44 patients treated with

surgery alone were evaluated, it was seen that 15.9% (n=7)

of these patients were stage 1, 40.9% (n=18) were stage 2,

and 43.2% (n=19) were stage 3. Adjuvant chemotherapy

with cisplatin/fluorouracil combination was administered to

27.3% (n=12) of the patients in this group.

One patient died in the intensive care unit due to surgical

complications in the postoperative period.

In the group of patients receiving definitive CRT, 1 patient

died due to complications during treatment.

The number of patients receiving preoperative CRT was 25

and the number of patients receiving postoperative CRT was

18 in the multimodal treatment group. In the multimodal

treatment group, a pathological complete response was

determined in 64% (n=16) preoperative CRT group. In this

group, 4 patients died in the postoperative period due to

complication. In postoperative CRT group, 11.1% (n=2) of the

patients were stage 1, 16.7% (n=3) were stage 2, and 72.2%

(n=13) were stage 3 after surgery.

The median follow-up time was 31 months (2-142) in the

surgical group, 11 months (2-106) in the definitive CRT

group, and 20 months (4-140) in the multimodal treatment

group.

The median disease-free survival was 21 months (95% CI 14-

27) in the surgical group, 8 months (95% CI 4-11) in the

definitive CRT group and 18 months (95% CI 0-39) in the

multimodal treatment group (p=0.059). DFS curve shown in

Figure 1.

Figure 1: Disease Free Survival

The 2-year disease-free survival (DFS) was 43% in the surgical

group, 33% in the definitive CRT group, and 47% in the

multimodal treatment group (p=0.05).

The median overall survival (OS) was 40 months (95% CI 0-

92) in the surgical group, 19 months (95% CI 15-22) in the

definitive CRT group and 54 months (95% CI 11-96) in the

multimodal treatment group. The difference between the

groups was statistically significant (p=0.012). Cumulative OS

curve shown in Figure 2.

The 2-year OS was 68% in the surgical group, 40% in the

definitive CRT group and 59% in the multimodal treatment

group (p=0.01).

In the multimodal treatment group, the median OS was

found to be 47 months (95% CI 0-99) in the preoperative CRT

group, and 64 months (NA) in the postoperative CRT group.

The difference between the groups was not statistically

significant (p=0.302). OS curve when the multimodal group

was divided into two as preoperative and postoperative CRT

shown in Figure 3.

DISCUSSION

Surgical resection is the basic method that is conventionally

effective in providing local disease control in non-metastatic

esophageal cancer treatment. However, due to high

locoregional recurrence and distant metastasis rates,

surgical resection alone is insufficient. The median overall

40

survival after esophagectomy is 15-18 months and the 5-

year survival rate is 20-25% [2].

Figure 2: Overall Survival

Figure 3: Overall survival in definitive chemoradiotherapy group

In a study by Orringer et al. conducted on 800 patients, the

5-year survival rates after esophagectomy were reported

23% [17]. In another study in which the surgery was

compared with surgery after preoperative CRT, and patients

were evaluated in the early stage, the median OS was

reported as 18.6 months in the patients who underwent

surgery [9].

In the present study, the disease-free survival was 21

months and the overall survival was 40 months in the group

of patients who underwent surgery alone. In the surgical

group, 27.3% of the patients (n=12) received adjuvant

chemotherapy with Cisplatin/Fluorouracil combination.

Compared to general literature data, the patients included

in the current study had longer DFS and OS. Possible reasons


41

for this may be the exclusion of upper esophageal tumors,

which are known to have a worse prognosis, and the fact

that approximately 25% of the patients who underwent

surgery were administered adjuvant chemotherapy.

Although surgical resection is still the basic standard

approach in non-metastatic esophageal tumors, definitive

chemoradiotherapy is still an effective local treatment

alternative for patients not suitable for curative surgery [18].

In one of the largest studies in which a direct comparison

was made between definitive chemoradiotherapy and

surgery, the two-year survival rates were 45.4% in the

definitive CRT group and 56.2% in the surgical group [19].

This study supports the idea that all patients who cannot

undergo surgery due to high risk may be recommended

definitive chemoradiotherapy independent of the histology.

In the present study, the definitive CRT group showed a

disease-free survival of 8 months, an overall survival of 19

months, and a 2-year survival rate of 43%. These results are

consistent with the literature.

Although surgical resection is the curative treatment

approach for esophageal cancer, the poor long-term survival

outcomes have encouraged multimodal treatment

approaches in this patient group. With preoperative

chemoradiotherapy as one of the multimodal treatment

methods, the treatment of micro metastases and regression

of the tumor stage contribute positively to the overall

survival rates of patients by increasing the rate of curative

resection [4-10].

In the CALGB 9781 study, the median survival was 4.4 years

vs. 1.7 years (p=0.002) and 5-year survival rates were

reported to be 39% vs 16% in favor of multimodal treatment

in esophagectomy after preoperative CRT, where the

cisplatin/fluorouracil combination was used compared with

esophagectomy only [10]. In the CROSS trial, patients who

underwent surgery after preoperative chemoradiotherapy

and patients who underwent surgery only were compared.

The concomitant paclitaxel-carboplatin combination was

used in this study. It was reported that the preoperative CRT

improved the survival times compared to the surgery group

(OS 49.4 months vs 24.0 months, HR for survival, 0.657; 95%

CI, 0.495-0.871; p=0.003) [4]. The long-term results of the

CROSS trial also showed that the contribution to overall

survival continued [12].

Another multimodal treatment approach is postoperative

adjuvant CRT. Many studies have shown the contribution to

survival of postoperative chemoradiotherapy in patients

who have undergone esophagectomy [13, 14, 20, 21, 22, 23].

In a study by Hwang et al., the 3-year OS rates in squamous

cell esophageal cancer were 44.9% in patients who

underwent postoperative CRT after esophagectomy, and

28.1% in patients who underwent surgery alone [20].

Following studies showing the contribution of preoperative

and postoperative CRT in esophageal cancer, questions were

asked about the prognostic contribution of surgery and the

sequence of chemoradiotherapy and what should be the

optimal treatment sequence. In a prospective study by Lv et

al., where preoperative CRT, postoperative CRT, and surgery

were compared, both 5-year OS (43.5% vs 42.3%) and 5-year

DFS (37.5% vs 37.2%) were found to be similar between the

preoperative CRT and postoperative CRT groups (p>0.05)

[16]. Chen et al. emphasized that CRT together with surgery

extended the overall survival independently of the

treatment sequence [24].

In a retrospective study in which Hsu et al. evaluated the

optimal treatment sequence for locally advanced

esophageal cancer in 2017, the preoperative CRT and

postoperative CRT groups were found to have similar

median OS (26 vs 23 months, p=0.31) [25]. A statistically

insignificant but clinically significant difference was found in

disease-free survival (16.7 months vs 10.4 months, p=0.061).

However, in that study, the rate of stage 3 patients was

higher in the group receiving postoperative CRT.

Based on this information, in the present study, the

multimodal treatment group was found to be superior to

patients who underwent surgery only or definitive CRT in

terms of both overall survival and disease-free survival. The

treatment sequence in the multimodal group was not found

to affect the overall survival and disease-free survival and

these results are consistent with the current literature.

Since the present study was retrospective, it has some

limitations. As patients from three different oncology clinics

were included, it was not possible to obtain information on

which criteria the patients were directed to different

treatment groups when the initial treatment plan was made.

No information could be obtained about why the patients

with local disease could not be operated on. The fact that

patients undergoing surgery were operated on by different

surgical clinics was another limitation. Not all toxicity data

could be obtained due to the retrospective nature of the

study.

In conclusion, it was determined that the multimodal

treatment of squamous cell medium and lower esophageal

tumors increased the disease-free survival and overall

survival, but the treatment sequence had no effect in this

particular. However, there are questions that still need to be

answered for operable esophageal tumors, such as what the

ideal local treatment modalities and combinations are,

whether it is preferable to apply the chemotherapy scheme

42

synchronously with CRT, and the location of postoperative

adjuvant chemotherapy. There is a need for further

randomized phase studies on these subjects.

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43


ORIGINAL ARTICLES

Methods of assessing stable coronary artery disease by non-invasive imaging techniques

Carmen M. Voicu1, Tiberiu Nanea2

Abstract: Diagnosis of stable coronary artery disease is vital for prognosis, classification and early treatment. Current guidelines show that patients with stable angina who are suspected of CAD need to undergo a certain protocol for classification and further analysis. This review’s aim is to present the most used non-invasive techniques for identification of CAD and to underline the current development of imaging technology and the possible reduction of invasive measures due to non-invasive techniques.

Currently, non-invasive techniques used to diagnose stable coronary artery disease have a very high accuracy and newer methods seem to be comparable to the gold-standard. The majority of the methods discussed have an optimal performance for patients with PTP between 15-85%, and the future of diagnosis for these patients seem to involve less invasive measures and less radiation by improving the current devices and by usage of machine-learning algorithms.

Keywords: coronary artery disease, PTP, stress echocardiography, SPECT, CMR, CCT

INTRODUCTION

Diagnosis of stable coronary artery disease is vital for

prognosis, classification and early treatment. Failure in doing

so, might determine secondary events such as: disease

progress, myocardial infarction or even death.

Current guidelines show that patients with stable angina

who are suspected of CAD need to undergo a certain

protocol for classification and further analysis.

This review’s aim is to present the most used non-invasive

techniques for identification of CAD and to underline the

current development of imaging technology and the possible

reduction of invasive measures due to non-invasive

techniques.

METHODS

A PubMed review was performed, analyzing all publications

from 1968 to 2019 concerning the topic “stable coronary

artery disease” (keywords: coronary artery disease, PTP,

stress echocardiography, SPECT, CMR, CCT). Human studies

and meta-analyses, published in English, were cited in this

review.

RESULTS AND DISCUSSION

Diagnosis and management

According to current guidelines, patients with suspected

SCAD will follow a step-by-step approach for confirmation.

After the clinical examination and basic tests applied (ECG,

bio-chemistry indicators, resting echocardiography), if the

cause of chest pain is none other than CAD and the left

ventricle ejection fraction is higher than 50%, the evaluation

of suspected SCAD commences (patients with LVEF<50%

have a high risk for cardiovascular events and they should

have ICA without further testing). [1]

First step is to determine the pre-test probability of SCAD

1 Clinical Emergency Hospital Bucharest, Romania 2 Prof. Dr. Th. Burghele” Hospital, Bucharest, Romania

44

(PTP). This indicator is evaluated by the age, gender and the

nature of symptoms for the suspected patient, and evaluates

the probability of having a coronary artery disease before

realizing any tests.

Non-invasive imaging techniques that assess coronary artery

disease usually have sensitivities and specificities around the

value of 85% (coronary computed tomography angiography

– coronary CTA has the highest sensitivity (95%) [2] while

stress echocardiography has the highest specificity (94.6%)

[3]). This is why for 15% of the patients, most imaging

techniques will be false positive and therefore, for these

patients (with PTP < 15%) performing no non-invasive

imaging tests will bring less incorrect results. Therefore:

patients with PTP < 15% will not do any further

investigations;

patients with PTP between 15-65% are recommended to

have an exercise ECG as the initial test and afterwards if

necessary, perform imaging tests;

patients with PTP between 66-85% must have a non-

invasive imaging test for confirmation;

patients with PTP over 85% are assumed to have SCAD, so

they don’t need further investigations. [1]

As such, patients with PTP between 15%-85% are required

to be assessed with non-invasive techniques for risk

stratification and selection for invasive measures

(revascularization or ICA). [4]

Electrocardiogram exercise testing

As described above, for patients with PTP within 15-65% for

suspected SCAD, an exercise electrocardiogram will be the

first and best option.

According to the Bruce protocol, this test involves using a

treadmill or an exercise bicycle in which patients are

monitored using a continuous 12-lead ECG and their blood

pressure measured, when they are exercising. The level of

difficulty increases incrementally every 3-minutes until a

certain target is reached (the predicted heart rate for the age

of the patient) or the patient cannot continue the test. [5]

If ST-depression is present with a value of ≥ 0.1mV or 1 mm,

in one or more ECG leads, which persist at least 0.06-0.08

seconds after the J-point, the test detects a possible CAD. [1]

Data shows that the usefulness of the test might come for its

higher specificity, one study shows a sensitivity of 45%, and

specificity of 85% [6] while another study shows higher

values for men (sensitivity – 40%, specificity – 96%) than for

women (sensitivity – 33%, specificity – 89%). [7]

Also, in a meta-analysis which compared the efficacy of

exercise stress testing between 34 studies, results also

showed that for men a positive exercise test results in a 89%

probability of CAD, and for women results in a 69%

probability of CAD. Whereas, a negative exercise test leads

for men to a 37% probability of CAD and for women to an

18%. These values show that a large share of patients may

be undetected after performing an exercise stress test. [8]

This method is useful only for patients that don’t have ECG

abnormalities at baseline. For example, patients with Wolff-

Parkinson-White syndrome, paced ventricular rhythm, LBBB,

use of digitalis, atrial fibrillation, left ventricular hypertrophy

with repolarization changes or digoxin use, have a higher

likelihood that the observed ST-segment depressions would

happen because of the baseline pathology and not the CAD.

Therefore, in these patients the ECG results aren’t

interpretable and exercise ECG testing should not be

performed. [9]

Despite all the results, for low-risk patients, for example

women, the standard ECG exercise treadmill test should be

the first diagnostic strategy, because of its availability and

lower costs of usage. Additional imaging techniques, like

myocardial perfusion imaging (MPI) does not add any

substantial benefit to the exercise treadmill test, but

increases diagnostic costs significantly [10].

Also, it is safe to say that during exercise testing, the risk of

having myocardial infarction because of the increase in the

pro-coagulant activity, doesn’t increase for patients with

CAD (objectified angiographically) in comparison to those

who don’t have CAD, meaning that the method is in general

safe. [11]

Although this method is accessible for diagnosis of CAD, in

the near future it will probably be replaced with other more

accessible, non-invasive imaging techniques. Cardio-

goniometry (3D-ECG) was demonstrated to have a higher

performance in diagnosis (sensitivity 75% vs sensitivity

68.1% - exercise ECG and specificity 74.4% vs specificity

38.1% - exercise ECG) of CAD in women, and being able to

have this efficacy without having to undergo stress-testing

and being practically free-of-risk, surely proves an

improvement in easiness and performance in the diagnosis

of CAD for the near future. [12]

Stress echocardiography

Another imaging technique for the assessment of stable CAD

is stress echocardiography. This method usually involves a

mechanical stressor (exercise performed on a treadmill or a

bicycle) or a pharmacological agent.

The principle of stress echocardiography is the identification

of functionality for all cardiac walls and further classification

into normal, ischaemic, viable or necrotic myocardium:


45

- normal myocardium responds with normokinetic function

at rest and during stress it may have a normokinetic or

hyperkinetic function;

- ischaemic myocardium may have a normal function at rest,

but during stress its response worsens, having a

hypokinetic/akinetic/dyskinetic function;

- viable myocardium testing in dysfunctional myocardium at

rest shows a improvement during stress response because it

would indicate a region of hibernating myocardium that

improves its function after revascularization;

- necrotic myocardium doesn’t improve its function during

stress, a region of dysfunctional myocardium at rest has its

function fixed. [13]

Stress echocardiography using exercise stress is preferable

because it provides additional data like exercise time,

workload, heart rate and blood pressure variability.

Pharmacological stress using dobutamine can be used for

patients who are unable to exercise. [1]

Also using dobutamine bring the advantage of assessment of

viability more accurately than exercise stress

echocardiography. Ischaemic but viable myocardium at low

doses of dobutamine (10-20 μg/kg/min) improves its

function, but at high doses (40 μg/kg/min) its function

worsens. This effect is due to the initial inotropic function of

dobutamine at low doses, whereas in high doses its function

changes to chronotropic and especially vasodilatory. [14]

Using additional contrast to the method (by using

microbubbles of encapsulated gas) can bring enhancement

of the images viewed, by improving image quality, accuracy

of detection of CAD and reader confidence, especially when

certain segments cannot be visualized at rest. [15]. Newer

data show data coronary microvascular dysfunction (a

potential cause for chest pain) can be observed using

myocardial contrast echocardiography, a marker for possible

CAD, patients with this issue having lower hyperemic

perfusion and microvascular flux rate than patients with

normal microvascular function. [16]

Diagnosis of CAD using stress echocardiography is quite

efficient. Exercise stress echo, dobutamine and dipyridamole

stress echo show sensitivities of 85%/80%/78% and

specificities of 77%/86%/91% for detection of CAD, which

are significantly better than electrocardiogram exercise

testing, and similar to SPECT [17]

Also, using strain-rate imaging and tissue Dopple imaging

can improve the quality of detection for CAD. Because the

interpretation of images in most echocardiographies are

subjective and prone to errors, measuring strain-rate can

determine an objective view on the diagnosis. Voigt et al

showed that ischemic segments had significantly higher peak

systolic strain-rates and strains during ejection time during

dobutamine stress than nonischemic segments [18] and

Gupta et al., recently showed in a meta-analysis similar

results, analysis of longitudinal strain imaging having higher

AUC-ROC prediction of CAD (0.92) than assessment of wall

motion (0.83). [19]

The newest advancement in echocardiography for detecting

CAD markers is the 3D-speckle tracking echocardiography

(3D-STE). One of the most used scoring systems to objectify

CAD severity is the Gensini score. In one study, using 3D-STE

to measure 4 parameters of CAD (global longitudinal strain –

GLS, global circumferential strain – GCS, global radial strain

– GRS and global area strain – GAS) it had been found that

patients found with critical CAD after coronary angiography

had significantly worse values of GLS,GCS,GRS,GAS than

patients with noncritical CAD. Also the Gensini score had a

significant positive linear correlation with GLS and GAD,

meaning that 3D-STE was a very good method do identify the

grade of severity of CAD. [20]

SPECT (Single photon emission computed tomography) –

Myocardial perfusion scintigraphy

One of the most used imaging techniques, uses similar

principles like the previously described methods. It uses

either exercise stress or pharmacological stress (e.g.

adenosine, dipyridamole, dobutamine, regadenoson) and

measures the level of uptake of radioactive tracers at rest

level and stress level from the myocardium. In ischemic

tissue, due to the lower blood flow in stress response, the

uptake of the tracer is reduced, meaning a positive test for

diagnosis of CAD. [4]

Standard radiotracers are Technetium-99m (99mTc) or

Thallium 201 (201Tl), although the latter has a higher

radiation dose. New developments in this technology

(cadmium-zinc-telluride – CZT) show a significantly higher

performance than conventional SPECT and a lower dose of

radiation. [21] Also another radiotracer (for PET) that is

frequently used is Rubidium 82 (82Rb) that is associated with

lower radiation exposure and high sensitivity (82%) and

specificity (90%) for detecting ischaemia. [22]

The method also compares ischaemic areas of myocardium

to normal areas. Some patients (with triple vessel disease)

whom hearts have a widespread ischemia, will be detected

false-negative for CAD because of the lack of inducing

ischemia in the underperfused myocardium, proving a

limitation of the method. [23]

Another limitation of the method would be diagnosis of CAD

in patients with left bundle branch block (LBBB). In those

patients, the intraventricular septum has a delay in

46

contraction (being dyskinetic), and in the moment of image

acquisition may have a lower thickness, indicating a LAD

territory ischaemia, and thus a false-positive result. [24]

Also, for asthmatic patients that are undergoing SPECT, using

adenosine is a contraindication because of the possible

precipitation of bronchospasm due to activation of all

adenosine receptors (especially A1, A2B and A3).

Regadenoson, a selective A2A agonist (for producing

hyperaemia) is currently used for these patients, because of

its sufficient hyperaemic response, less side effects, and

comparable efficacy to adenosine. [25]

The REASSESS study, in which in a prospective manner was

assessed the diagnostic performance of coronary computed

tomography angiography (CTA) vs. SPECT, showed that

although many cases of stable CAD wouldn’t have been

diagnosed by SPECT if invasive measures (angiography)

wouldn’t have been taken, the overall performance of both

of the methods (CTA and SPECT) was similar, in objectifying

hemodynamically significant stenosis, having a similar

accuracy (70% - CTA vs. 68% SPECT). [26]

The issue of false-negative results in SPECT, although

present, is indicated to have a low prevalence and thus, a

low impact. For example, in 133 patients with normal SPECT

results, only 16% had anatomically and functionally

significant stenoses, and from 180 vessels analyzed with

normal SPECT results, only 8.33% had stenoses. As such, the

prevalence of false-negative cases in normal SPECT remains

low and a normal result stays important in diagnosis and

follow-up. [27]

SPECT also predicts efficiently long-term outcomes. Patients

with ischaemia burden, who had SPECT and also underwent

early coronary revascularization had significantly lower all-

cause mortality and cardiac mortality in comparison to

patients who received only pharmacological therapy,

indicating a significant diagnostic value for the severity of

CAD by using SPECT. [28]

Usage of myocardial perfusion scintigraphy combined with

positron emission tomography is more accurate in

comparison to SPECT, having higher sensitivities (90% - PET,

85% - SPECT) and higher specificities (88% - PET, 85% -

SPECT), also AUC-ROC prediction was higher for PET (0.95) in

comparison to SPECT (0.90), according to Mc Ardle et al. [29]

A similar study showed better image quality and diagnostic

accuracy of CAD for PET in comparison to SPECT (showing a

percentage of 78%/79% excellent image quality of

rest/stress PET scans vs. 62%/62% excellent image quality of

rest/stress SPECT scans). [30]

Data also shows that using PET-MPI to determine myocardial

blood flow is excellent and superior to the relative

measurement of tracer uptake, being more efficient for the

detection of CAD and eliminating false-negative patients

with balanced ischaemia (triple vessel disease). [31]

New technology in PET-MPI for diagnosis of CAD show

similar results as described above, for usage of flurpiridaz 18F

in comparison to SPECT, bringing more advantages for PET-

MPI (higher quality images, diagnostic certainty of

interpretation, and sensibility of detection of CAD). [32]

Cardiac magnetic resonance

One of the most advantageous methods of imaging

techniques, because of the high-detail images, non-

invasivity and lack of any ionizing radiation, cardiac magnetic

resonance can identify CAD, even better than the previous

methods discussed. Similar to all CAD detection methods, is

uses a stress agent, exercise or pharmacological.

Stress cardiac magnetic resonance using both a bicycle [33]

and a treadmill [34] seems feasible for detection of CAD.

Recently, the EXACT study, which used stress CMR with a

treadmill, showed a sensitivity of 79% and a specificity of

99% for detection of CAD after using a SPECT, also showed

higher agreement of diagnosis with angiography (k=0.82)

than SPECT (k=0.46), demonstrating as such excellent

diagnostic value. [35]

Pharmacological stress uses a vasodilator (adenosine or

regadenoson) or dobutamine. Added in the vasodilator

method is the administration of i.v. gadolinium contrast, to

enhance the perfusion defects that can be seen in ischaemic

walls. Using dobutamine requires a similar method like in

stress echocardiography, by viewing wall motion

abnormalities in ischaemia response. [36]

In CMR the assessment of CAD can be either qualitative (by

visual assessment of presence and degree of ischaemia) or

quantitative by measuring absolute blood flow. A recent

study showed that quantitative analysis had similar

diagnostic accuracy (83%) as qualitative (80%) and observers

considered a better approach to diagnose CAD using

quantitative CMR. [37]

Recent data showed that CMR stress with perfusion in

comparison with SPECT and PET showed good diagnostic

accuracies, having a sensitivity of 89% (in comparison to

SPECT – 88%, and PET – 84%) and a specificity of 76% (in

comparison to SPECT – 61% and PET – 81%). Authors also

considered that CMR could be a good alternative to PET,

having a similar diagnostic accuracy. [38]

Nevertheless, current data shows that perfusion CMR has a

better diagnostic performance value than SPECT, as shown


47

in the MR-IMPACT trial [39]. Also, the CE-MARC study

showed that CMR had better sensitivities than SPECT (88.7%

for men vs. 50.9% for men – SPECT and 85.6% for women vs.

70.8% for women – SPECT) and similar specificities, and

better diagnostic accuracies. [40]

The CE-MARC 2 study compared the efficacy of CMR, NICE

guidelines and SPECT in reducing the percentage of

unnecessary angiographies in patients with suspected

angina. The results showed that the CMR strategy

determined a lower probability of unnecessary

angiographies within 12 months than the NICE guidelines

strategy, CMR and SPECT reducing significantly the number

of angiographies in comparison to NICE guidelines. [41]

The adverse effects for gadolinium-based contrast agents

used in CMR have a low frequency (0.36%), the severe are

even less (0.033%), and these adverse effects are more

physiological than allergic (most frequently were dyspnea,

hypersensitive reactions and emesis). [42].

Similar to SPECT, it had been shown that CMR can have long-

term prediction values. Newer technology in CMR measures

GLS (global longitudinal strain), this marker can be an

independent predictor for long-term major adverse cardiac

events (MACE): heart failure hospitalization, myocardial

infarction, sustained ventricular tachycardia or death, in

pacients with known or suspected coronary artery disease.

That means CMR can identify patients with high risk of

having dangerous adverse events in the near future because

of CAD. [43]

Also, the newest data shows that CMR with quantitative

myocardial perfusion mapping can detect coronary

microvascular dysfunction separately from CAD, with high

AUC-ROC prediction values (0.95 on vessels with MVD) with

high sensitivity (90%) and specificity (89%), almost

comparable with invasive procedures. [44]

More powerful magnets (3.0 Tesla), although not so widely

available, used on CMR machines, have a net superiority

over 1.5 Tesla CMR, having a far greater AUC-ROC prediction

value (0.963 vs 0.645), sensitivity (90.5% vs. 61.9%) and

specificity (100% vs. 61.9%). [45]

Computed tomography

Multidetector row CT systems used in cardiac CT are

sufficient enough to visualize coronary anomalies, although

this last method is preferable for measuring coronary

anatomy and pathology occurring in this matter. There are

two methods of using CT in the benefit of diagnosis for CAD:

calcium scoring and CTCA (coronary computed tomography

angiography).

Calcium scoring uses the principle of identifying coronary

calcification, without use of contrast. Any pixel above 130

Hounsfield units is defined as coronary calcification and can

be quantified using the Agatston score, which is dependent

by the size of the plaque and the radiographic density. [46]

However, there can be identified obstructive coronary

lesions which may be not calcified and vice-versa, critically

calcified coronary arteries which aren’t yet obstructed.

Because of this matter, the preferable way to diagnose CAD

is CTCA.

The North American Society for Cardiovascular Imaging

(NASCI) agreed in their guidelines that patient selection is

needed before usage of CTCA. As such:

- because of contrast usage, any patients with known

history of severe anaphylactic reactions to contrast, have

contraindication to this method;

- patients with history of acute myocardial infarction, severe

hypotension, decompensated heart failure or renal

impairment have also contraindication to this method;

- pregnant women or patients who are unable to cooperate

to the breath-hold instructions are not able to have CTCA.

[47]

The method involves usage of a bolus of contrast injected

i.v., and after that realizing a coronary angiogram with

complementary ECG gating. The ACCURACY trial showed

that CTCA in comparison to ICA (invasive coronary

angiography) had similar performances in measurements

(CTCA sensitivity – 95% vs. 94%, CTCA specificity 83% vs.

83%, CTCA positive predictive value – 64% vs. 48% and CTCA

negative predictive value 99% vs. 99%) for diagnosis of CAD

with 50%/70% stenosis. [2]

Although the main issue in this non-invasive technique is

usage of radiation and scan preparation, another problem is

that presence of heavy calcification (objectively measured

by an Agatston score > 400) in case of patients with severe

CAD lowers the specificity, by creating beam hardening

artefacts and excessive image noise. [48]

Analysis of outcome data, such as in the PROMISE trial,

showed that patients with suspected CAD who did CTCA had

in long-term observation, fewer catheterizations than

patients who were functionally tested (using exercise

electrocardiography, stress echocardiography or nuclear

stress testing) although these patients hadn’t any

improvement in clinical outcome. [49], and also the SCOT-

HEART trial showed that usage of CTCA reduced fatal and

non-fatal myocardial infarction but not significantly in

patients with suspected CAD. [50]

Improving the current performance in CTCA is possible. One

48

method is measuring tthe fractional flow reserve (CTFFR).

Although it is highly time-consuming and requires computer

modeling, data shows that usage of CTFFR in CTCA is

beneficial, increasing the diagnostic accuracy in comparison

to standard CTCA. [51]

Additional usage of β-blockade and nitroglycerin before the

exam seem to increase the diagnostic performance [52] and

newer data show that CTFFR-CTCA is a safe alternative to ICA

with a significantly lower rate of ICA in comparison to

functional testing (61% cancelling rate), therefore lowering

the clinical cost and having the same clinical outcomes. [53]

Machine-learning (based on a deep learning model) in

CTFFR-CTCA seems to also make better the standard

procedure, by reclassifying patients with nonsignificant

stenosis and raising overall diagnostic accuracy (from 71% to

85%). [54]

CONCLUSION

Currently, non-invasive techniques used to diagnose stable

coronary artery disease have a very high accuracy and newer

methods seem to be comparable to the gold-standard. The

majority of the methods discussed have an optimal

performance for patients with PTP between 15-85%, and the

future of diagnosis for these patients seem to involve less

invasive measures and less radiation by improving the

current devices and by usage of machine-learning

algorithms.

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51


CLINICAL PRACTICE

Endoscopic eradication of nodular gastric vascular antral ectasia by using band ligation after argon plasma coagulation

Sandica Bucurica1,2, Mihaela Ailenei1, Mariana Jinga1,2, Florentina Ioniță Radu1,3

Abstract: Gastric antral vascular ectasia (GAVE) is an important cause of gastro-intestinal bleeding. The most common clinical presentation of GAVE is chronic occult bleeding that leads to symptomatic iron deficiency anemia, but some cases could present with acute massive bleeding. Frequently, patients are dependent by iron suplimentation, or in severe cases even blood transfusions. Endoscopic therapy is frequently necessary in acute or chronic blood loss. Over the past several years, treatment for GAVE has continued to evolve as the number of available effective therapeutic interventions has increased. These included: YAG laser, argon plasma coagulation (APC), endoscopic band ligation, cryotherapy and surgical anterectomy. Argon plasma coagulation is the most commonly used technique, but has been associated with several complications like sepsis, post-APC bleeding, gastric outlet obstruction and increased incidence of hyperplastic polyps. Endoscopic band ligation (EBL), a mechanical procedure, has been reported in the past years as an effective salvage therapy for GAVE that is refractory to other approaches, or even as the first line treatment. We present a case of nodular GAVE treated succesfully with endoscopic band ligation after unsuccesufull sessions with argon plasma coagulation.

Keywords: gastric antral vascular ectasia, endoscopic band ligation, Argon plasma coagulation, gastro-intestinal bleeding

INTRODUCTION

Gastric antral vascular ectasia (GAVE) or “watermelon

stomach” is a relatively rare cause of gastrointestinal (GI)

bleeding that mainly affects women aged 70 years and older.

The incidence is estimated to be aproximately 4% of upper

GI bleeding [1]. The term "watermelon stomach" is derived

from the characteristic endoscopic appearance of

longitudinal rows of flat, reddish stripes radiating from the

pylorus into the antrum that resemble the stripes on a

watermelon [2].

It usually presents as occult bleeding with chronic iron

deficiency anemia. Even though GAVE was first diagnosed

about six decades ago, its etiopathogenesis has not been

fully established yet, with many hypotheses proposed such

as mechanical stress, hormonal factors, and autoimmune

factors. It is associated with liver cirrhosis, autoimmune

disease, connective tissue disorders and collagen vascular

disorders (eg, systemic sclerosis, Sjogren syndrome), chronic

renal failure, bone marrow transplantation, acute myeloid

leukemia and heart disease.

Frequently GAVE patients have chronic GI bleeding, but

sometimes it can cause severe acute life-threatening

bleeding especially in elderly with multiple chronic medical

illnesses [2].

GAVE is typically located in the gastric antrum; however, it

may be also found rarely in other areas of the GI tract,

including cardia, duodenum, jejunum, and rectum. The

1 Carol Davila University Emergency Central Military Hospital, Bucharest, Romania 2 Carol Davila university of Medicine and Pharmacy, Faculty of General Medicine, Bucharest, Romania 3 Titu Maiorescu University, Bucharest, Romania

Corresponding author: Ailenei Mihaela

[email protected]

52

involvement of the proximal part of the stomach is very rare

and commonly located within a diaphragmatic hernia.

At endoscopy, GAVE may appear as 2 types. First type is the

diffuse punctuate lesions in the antrum typically seen in

male patients with cirrhosis and commonly accompanied by

acute bleeding. Second one is the red lesions organized in

stripes radially departing from the pylorus, known as

“watermelon stomach”, mostly common in females with

connective tissue diseases and usually present with occult

bleeding [1].

Histopathologically, GAVE is characterized by vascular

ectasia, spindle cell proliferation, and fibrohyalinosis.

Immunohistochemical staining for CD61, a platelet marker,

further confirms a diagnosis of GAVE [3].

Over the years, treatment for gastric antral vascular ectasia

(GAVE) has continued to evolve and the number of available

treatments has continued to increase, including surgical,

medical and endoscopic therapies

Medical therapy has not clearly shown satisfactory results.

Multiple drugs, such as hormonal (estrogen-progesterone)

therapy, steroids, octreotide and tranexamic acid, have been

tried to control GAVE-related bleeding. After all, no one has

clearly shown satisfactory results in order to consider

medical therapy as a valid alternative to an invasive

approach.

Endoscopic therapies have rapidly become the first line

therapy with argon plasma coagulation (APC) as the most

common used method and more recently with

radiofrequency ablation system (RFA) using Halo90 catheter

and endoscopic band ligation (EBL). Both of them have been

shown to be safe and effective for GAVE treatment. The

latter two have been utilized in treatment of severe, diffuse,

APC refractory GAVE. The clinical outcomes of ablative

therapy such as APC treatment or HALO90 system were

reported as 80%-100% success rate.

Other therapies include Nd:YAG (neodymium:yttrium-

aluminum-garnet) laser coagulation, but with a higher risk of

perforation given the deeper thermal effect. Endoscopic

sclerotherapy, heater probe, cryotherapy have also been

described in the literature. For unresponsive cases to

endoscopic therapy, surgery with antrectomy can be

considered but carries a high surgical risk, especially in the

cirrhotic patients.

APC is most commonly used method, but has been

associated with sepsis, post-APC bleeding, gastric outlet

obstruction and increased incidence of hyperplastic polyps’

formation. It is needed multiple sessions of APC to reduce

bleeding episodes and/or decrease transfusion dependence.

APC has been found to be equally effective in the treatment

of GAVE and is superior to ND:YAG laser in cost, convenience

and complication rates(4).

The non-ablative treatment options is the endoscopic band

ligation. EBL was firstly reported as the treatment for

refractory GAVE in the patients who failed other treatment

modalities such as APC or hormonal therapy by Sinha et al.

[5]

Endoscopic band ligation has been reported as an alternative

effective endoscopic therapy and the rate of complication is

low in comparison with those reported for APC in

retrospective studies [6].

A case series of 9 patients reported by Wells et al also

showed superiority of EBL over endoscopic thermal therapy,

which were APC and bipolar thermal probe therapy, for the

rate of re-bleeding, duration of hospitalization and post

procedure transfusion. The complications reported for this

procedure were very small. Band ligation was prefered as

the first line treatment regarding of the extensive

involvement of the lesion in the patients. According to the

result of the treatment mentioned above, endoscopic band

ligation could be considered as first line treatment options

for the GAVE patients especially for extensive area of

involvement. [7]

A recent prospective study showed endoscopic

improvement with the use of endoscopic band ligation in

91% of the patients, with a significant improvement in the

hemoglobin and ferritin levels. Band ligation in GAVE has

been associated with transient abdominal pain in a minority

of the patients, but no major complications have been

reported in the literature. [9]

Some studies suggest that the number of sessions required

for GAVE eradication is inferior when using EBL compared to

APC, resulting in inferior health care costs. However,

randomized controlled trials are lacking to determine

whether EBL is more cost effective than APC as the primary

endoscopic therapy for GAVE. [9, 10]

Although initial reports of these endoscopic modalities are

encouraging, well-performed, larger, prospective studies are

needed before providing any definitive conclusion.

CASE PRESENTATION

Clinical data

We present a case of a 57-year-old female, diabetic with

multiple microvascular complications – diabetic polineuro-

pathy and chronic renal disease, hypertensive, with

moderate hypochromic microcytic anaemia and a positive


53

fecal occult blood test (FOBT), already in treatment with iron

therapy who presented for abdominal pain, fatigability,

phisical astenia and arthralgias. She denied no change in

weight, bowel pattern, or stool color. The physical

examination revealed paleness of the skin and mucosa and

otherwise unremarkable.

Laboratory data

Labs indicates a moderate hypochromic microcytic anaemia

(hemoglobine level – 9.4 g/dL, mean corpuscular volume –

70.2 fL, hematocrit – 31.1%, mean corpuscular hemoglobin

– 21.2 picog and sideremia – 26 microg/L.

Endoscopy

Superior digestive endoscopy showed hypertrofic gastric

antral vascular ectasia with mucosal eryhema, friability and

visible small vessels extending radially in linear rows

throughout the antrum and a duodeno-gastric reflux. She

underwent serial argon plasma coagulation treatments and

a second gastroscopy was performed next day which

showed post argon plasma coagulation ulcers which were

biopsied.

Histopathology data

Ulcer post argon plasma coagulation biopsy performed

showed modifications of chronic inactive gastritis, but GAVE

was not confirmed on biopsy.

Evolution

After two months and with iron therapy, the hemoglobin

level was normalised (12.7 g/dL) with low mean corpuscular

volume and mean corpuscular hemoglobin. At the

endoscopic examination the macroscopic appearance

persisted with multiple friable hypertrofic and nodular antral

vascular ectasia and duodeno-gastric reflux.

At 3 months follow-up, hemoglobin level mantained in the

normal interval (13.5 g/dL), but the endoscopic appearing

was worst, with larger, friable, with edema and hypertrofic

gastric atral vascular ectasia (Figure 1). We decided to apply

6 elastic bands on the biggest lesions with success (Figure 2).

No complications of the procedure were reported, and the

patient was discharged after 24h.

Figure 1: Endoscopic appearance from the index endoscopy, demonstrating multiple erythematous friable antral hypertrophic and

nodular lesions, representing nodular gastric antral vascular ectasia (GAVE)

Figure 2: Endoscopic image from the band ligation of GAVE

Two months later, hemoglobin level was stable (13.4g/dL).

The upper endoscopy revelead small hyperemic antral

circumferential disposed lesions with no signs of bleeding

and no hypertrophy, with almost complete eradication of

GAVE (Figure 3).

DISCUSSION

GAVE is a poorly understood entity, of unknown etiology,

and an increasingly identifiable cause of chronic iron

deficiency anemia. The pharmacological management of

54

GAVE had only poor results, so the mainstay of GAVE

management remains endoscopic therapy.

Figure 3. Endoscopic appearance 2 months after endoscopic band

ligation

Figure 4. Suggested flow chart for treatment algorithm [14].

GAVE: Gastric antral vascular ectasia; APC: Argon plasma

coagulation; RFA: Radiofrequency ablation; EBL: Endoscopic band

ligation.

APC is a modality of non-contact electrocoagulation that

applies high-frequency energy into tissue to cause thermal

effects, which has been used successfully to treat GAVE with

an effective transient response, but primary failure rates of

therapy of up to 14% have been reported. Some authors

suggest that this endoscopic method is insufficient in order

to achieve medium and long-term treatment success, as it

has been associated with a high recurrence rate (40–100%)

[11].

In addition, APC might have complications, such as sepsis,

pyloric stenosis and gastric outlet obstruction syndrome, in

20–33% of the patients [12].

EBL has been reported to be a relatively easy technique for

GAVE therapy, has been shown to be safe and effective with

lower complication rates in comparison with APC. Both Sato

et al. [6] in 2012 and Prachayakul er al. [13] in 2013 conclude

that EBL may be useful in the treatment of GAVE, to avoid

the high recurrence rate after APC.

In this case, the patient was initially treated with APC after

being diagnosed with GAVE as the cause of iron deficiency

anemia, but this strategy was not successful. APC treatment

might not be effective in some cases, especially in the case

of hypertrofic and nodular type of GAVE, and this could be

explained by the limited depth of thermal injury.

Since the histological changes are present in the mucosa and

submucosal layer, EBL may be more effective for GAVE

because of its ability to obliterate the submucosal vascular

plexus like for esophageal varices. In this patient, the

presence of extensive areas of the antrum affected with a

high-density of both mucosal and submucosal vascular

malformations is a likely explanation for the primary failure

of the APC treatment.

It is becoming apparent that patients with severe, diffuse or

refractory disease require multimodal therapy. Our case not

only shows that, but also that patients specifically with

nodular variant GAVE require and respond well to

multimodal therapy.

References:

1. Dulai GS, Jensen DM, Kovacs TO, Gralnek IM, Jutabha R.

Endoscopic treatment outcomes in watermelon stomach patients

with and without portal hypertension. Endoscopy. 2004;36:68-72.

2. Selinger CP and Ang YS. Gastric antral vascular ectasia (GAVE):

An update on clinical presentation, pathophysiology and treatment.

Digestion 2008; 77: 131–137

3. Westerhoff M, Tretiakova M, Hovan L, Miller J, Noffsinger A,

Hart J. CD61, CD31, and CD34 improve diagnostic accuracy in gastric

antral vascular ectasia and portal hypertensive gastropathy: an

immunohistochemical and digital morphometric study. Am J Surg

Pathol. 2010;34:494-501.

4. Naga M, Esmat S, Naguib M, Sedrak H. Long-term effect of argon

plasma coagulation (APC) in the treatment of gastric antral vascular

ectasia (GAVE) Arab J Gastroenterol. 2011;12:40–43.

5. Sinha SK, Udawat HP, Varma S, Lal A, Rana SS, Bhasin DK.

Watermelon stomach treated with endoscopic band ligation.

Gastrointest Endosc. 2006;64:1028–103

6. Sato T, Yamazaki K, Akaike J. Endoscopic band ligation versus

argon plasma coagulation for gastric antral vascular ectasia

associated with liver diseases. Dig Endosc 2012; 24: 237-242


55

7. Wells CD, Harrison ME, Gurudu SR, Crowell MD, Byrne TJ,

Depetris G, Sharma VK. Treatment of gastric antral vascular ectasia

(watermelon stomach) with endoscopic band ligation. Gastrointest

Endosc. 2008;68:231–236.

8. Kumar R, Mohindra S, Pruthi HS. Endoscopic band ligation: a

novel therapy for bleeding gastric antral vascular ectasia.

Endoscopy. 2007;39 Suppl 1:E56–E57.

9. S. Zepeda-Gomez, R. Sultanian, C. Teshima, G. Sandha, S. Van

Zanten, A.J. Montano-Loza, Gastric antral vascular ectasia: a

prospective study of treatment with endoscopic band

ligation,Endoscopy, 47 (2015), pp. 538-540

10. J. Keohane, W. Berro, G.C. Harewood, F.E. Murray, S.E.

PatchettBand ligation of gastric antral vascular ectasia is a safe and

effective endoscopic treatment, Dig Endosc, 25 (2013), pp. 392-396

11. S.M.A. Nakamura, H. Konishi, I. Oi, K. Shiratori, S. SuzukiLong-

term follow up of gastric antral vascular ectasia treated by argon

plasma coagulation, Dig Endosc, 18 (2006), pp. 128-133

12. E. Swanson, A. Mahgoub, R. MacDonald, A. ShaukatMedical and

endoscopic therapies for angiodysplasia and gastric antral vascular

ectasia: a systematic review, Clin Gastroenterol Hepatol, 12 (2014),

pp. 571-582

13. Prachayakul V, Aswakul P, Leelakusolvong S. Massive gastric

antral vascular ectasia successfully treated by endoscopic band

ligation as the initial therapy. World J Gastrointest Endosc 2013; 5:

135–137.

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Peng Li, Kondal Kyanam Kabir Baig, Charles Mel Wilcox, Shajan

PeterWorld J Gastrointest Endosc 2018 January 16; 10(1): 30-36.

56


CLINICAL PRACTICE

Death due to a rare posttraumatic complication: fat embolism

Cristina Podilă1, Mihaela C. Șomlea2, Bogdan A. Buhaș3, Adrian S. Judea4, Andreea A. Hleșcu5, Nicolae Nicoară4, Flavia Săndoiu1, Paula Marian6, Bianca Hanganu5, Irina S. Manoilescu5,7

Abstract: Fat embolism is a rare complication of high or medium intensity trauma. It is caused by the formation of fat particles in the territories of small terminal circulation, especially at pulmonary, tegumentary and cerebral levels. The mechanism underlying the fat embolism is described by several different theories in literature. In legal medicine, fat embolism raises many controversies upon the diagnostic certainty of the thanatogenerator mechanism leading to death. The occurrence of fat embolism syndrome followed by death must be properly explained so that the fatality can be adequately framed from a legal point of view. In this paper the authors present three cases in which victims of trauma died due to clinically undiagnosed fat embolism, the diagnosis being established only by postmortem histopathological examination. The authors underline the fact that the diagnosis of fat embolism syndrome, although it is a clinical one, it is often established only during autopsy.

Keywords: fat embolism, trauma, death, autopsy, diagnosis

INTRODUCTION

Embolism represents the motion through circulatory blood

flow of a material which is not present in blood in normal

conditions and its subsequent lodging inside the blood

vessels. In the case of fat embolism, the material carried

through the blood is represented by fat particles that reach

the level of microcirculation. Fat embolism syndrome

represents the systemic manifestation of the fat particles

being present inside the microcirculation.

Fat embolism was first described by Zenker in 1862 in the

case of a railroad worker who died of crushing injuries. In

1873 Bergmann diagnosed fat embolism in a living patient

who had suffered a fracture of the femoral bone [1, 2].

The causes of fat emboli formation are multiple, both

traumatic and non-traumatic. The most frequent traumatic

causes are: long bone fractures, orthopedic procedures, soft

tissue trauma (fat tissue laceration), liposuction and

mastectomy, neurosurgical interventions. Non-traumatic

causes include: acute pancreatitis, extensive burns,

diabetes, fatty liver due to diets rich in extrinsic fats and oils

[2, 3]. Exceptionally, fat embolism has been observed in

cases of hepatic steatosis (in alcoholics and diabetic patients

with hepatic damage) due to the destruction of hepatocytes

and subsequent release of fat particles [4, 5].

1 Bihor County Forensic Service, Oradea, Bihor, Romania 2 County Clinical Emergency Hospital Cluj-Napoca, Clinical Department of Dermatovenerology 3 County Emergency Hospital of Oradea, Department of Urology, Oradea, Romania 4 University of Oradea, Faculty of Medicine and Pharmacy, Department of Morphological Disciplines, Oradea, Romania 5 Grigore T. Popa University of Medicine and Pharmacy of Iasi, Romania, Department of Legal Medicine 6 University of Oradea, Faculty of Medicine and Pharmacy, Department of Medical Disciplines 7 Institute of Legal Medicine of Iași, Romania

Corresponding author: Andreea A. Hleșcu

[email protected]


57

Fat embolism occurs in 90% of patients who have suffered a

trauma, but only 2-5% of them develop the fat embolism

syndrome; particularly at risk are those with fractures of the

long bones. It is difficult to estimate the duration of this

syndrome because the symptoms are often subacute or

masked by other symptoms of trauma [2, 3].

Post-mortem studies have shown a different but a very high

incidence of fat embolism. Thus, a study by Behn C. et al. on

527 autopsies demonstrated the presence of fat embolism

in 92 of these [6]. Another study conducted by Hiss et al. in

1996, on 53 victims of aggression followed by death, showed

a high incidence of fat embolism. All the subjects studied

were young, male, victims of aggressions, suffering severe

trauma 24 hours before death. In thirty two cases the

presence of fat embolism was observed in the main organs,

with no other obvious cause of death. The authors of the

study hypothesized that the source of fat embolism was the

mechanical disintegration of the subcutaneous adipose

tissue [7].

In cases of fat embolism there is a poor correlation between

post-mortem and clinical findings. This discrepancy

ultimately gave rise to the concept of "iceberg effect of fat

embolism" [8- 12]. This justifies, as well as cases with a

insufficiently outlined clinical picture for a particular

pathology, or a clinical picture that cannot explain the

occurrence of death, the importance of forensic autopsy and

postmortem laboratory investigations (histopathological

and toxicological) in order to establish the thanatogenerator

mechanism and the causal link between trauma / illness and

death, and ultimately the legal nature of the case, i.e.

suicide, accident or homicide [13- 19].

MATERIALS AND METHODS

We present three cases of trauma in which the cause of

death was the fat embolism syndrome. All the cases are

characterized by a rapid clinical deterioration leading to

death, so that a clinical diagnosis of fat embolism syndrome

could not be established antemortem.

Case no. 1

Male, 72 years old, chronic alcohol consumer, with past

medical history of left femoral fracture and right sided

craniotomy, is admitted to hospital for head trauma. At the

time of admission physical examination revealed multiple

ecchymoses, pain at the pelvic level, lower limbs and

abdomen. Clinical and paraclinical investigations established

the following diagnosis: minor craniocerebral trauma, facial

trauma, posttraumatic subarachnoid hemorrhage, dura

mater hygroma, abdominal contusion, pelvic contusion.

Surgical intervention was performed to evacuate the dura

mater hygroma 6 days after the admission. Evolution was

initially favorable. On the 4th postoperative day, the patient

developed a febrile syndrome. Laboratory analysis

highlighted: elevated leucocyte count (13.390 of which

11.270 neutrofils); elevated serum amylase (225 U/L);

lowered erythrocyte count (3.83 milion); hematocrit levels

as low as 40.08 %; low thrombocytes count (137.700);

increased level of the liver enzyme AST to 48 U/L; low

creatinine serum levels (0.69 mg/dl) and reduced glomerular

filtration rate to 85 mil/min/1.73 m2. The next day the

patient suffered cardiorespiratory arrest that did not

respond to resuscitation maneuvers, followed by death. The

forensic autopsy was performed. The external examination

of the body showed: multiple injuries denoting violence such

as ecchymoses and abrasions; signs of medical treatment at

the level of the skull, i.e. recent surgical incision and an old

whitish scar. The internal examination showed: on the head,

2 craniotomy areas, one of them being recent, subarachnoid

hemorrhage, areas of flaccid cerebral structure, small

petechial hemorrhagic areas disseminated throughout the

brain. The examination of the lungs showed: pulmonary

stasis and edema, and areas of pulmonary condensation.

Fragments of brain and lungs were harvested during autopsy

and subsequently examined by optic microscopy using the

Sudan III staining. The microscopic examination revealed fat

emboli in the brain and lungs. Following the postmortem

macroscopic and microscopic examination we established

that the cause of death was the fat embolism syndrome.

Case no. 2

Male, 54 years old, was admitted to the hospital with the

diagnosis of: head trauma (subarachnoid hemorrhage,

fracture of the left temporal bone with extension to the

mastoid bone), face trauma (fracture of right jaw,

comminuted fracture of the nose) and chest trauma (left

pneumothorax, multiple rib fractures).

The patient was hospitalized for 35 days, during which

multiple pleurotomies and bronchoscopies were performed.

Laboratory examinations showed: increased leucocyte count

(25.170 of which 21.100 neutrofils); low red blood cell count

(2.612 milions); low hematocrit (21.240 %); low hemoglobin

level (7.793 g/dl); normal thrombocyte count; increased

level of AST (103 U/L); increased serum creatinine (4.28

mg/dl); increased GGT levels (93 U/L) and reduced

glomerular filtration rate (10.8 mil/min/1.73 m2). Clinical

evolution was initially favorable. On day 34 after admission

the patient developed a feverish syndrome. The next day he

suddenly suffered cardiorespiratory arrest, followed by

death. A forensic autopsy was performed. The external

examination of the cadaver revealed bruises and signs of

58

recent medical treatment. The internal examination

showed: linear head fracture, subdural hematoma under

partial resorption, small petechial hemorrhagic areas in the

brain, pulmonary edema, and areas of pulmonary

condensation. Fragments of organs were harvested (brain,

lung) and examined by optic microscopy using Sudan III

staining. Following the macroscopic and microscopic

examinations we concluded that the cause of death was the

fat embolism syndrome.

Case no. 3

Male, 20 years old, victim of a traffic accident, was admitted

to the hospital with the diagnosis of: polytrauma due to road

traffic accident, major craniocerebral trauma with diffused

cerebral edema, multiple rib fractures, fracture of the left

iliac wing and left ischial bones, fracture of the left femoral

neck, and type III A fracture of the femoral diafisis. Patient

was admitted in the hospital for 7 days and underwent a

surgical intervention for the femoral fracture. During the

first days after the surgery the patient was hemodynamically

stable. On day 4 the patient showed tachypnea, tachycardia,

and fever and his clinical condition suddenly worsen. The

laboratory examinations showed: low leucocyte count (1.56

of which 1.37 neutrofils); reduced numbers of erythrocytes

(2.31 milions); low hematocrit (23.3%); low hemoglobin

(6.77 g/dl); reduced number of thrombocytes (58.600/

mmc); increase in liver enzyme AST (272 U/L) and ALT (250

U/L); increased serum creatinine (2.43 mg/dl); increased

serum urea (94.16 mg/dl) and reduction of glomerular

filtration rate to 27.21 mil/min/1.73 m2. Death occurred on

the same day. At autopsy, the external examination of the

corpse revealed: multiple ecchymoses, abrasions,

hematomas, signs of medical treatment. The internal

examination showed: brain contusion; multiple rib fractures;

pulmonary edema, pulmonary condensation areas,

pulmonary infarction; fractures of the pelvis and of the left

femor. The microscopic examination of the fragments of

brain and lungs collected during the autopsy and stained

with Sudan III showed fat embolism. Therefore, based on

macroscopic autopsy findings and histo-pathological

examination of the brain and lung fragments, we established

that the cause of death was the fat embolism syndrome.

RESULTS

In all the three cases the victims suffered various trauma: in

the first case the victim suffered soft tissues and head

injuries, in the second case the victim suffered a polytrauma

with multiple fractures and soft tissue injuries and in the

third case the victim suffered craniocerebral trauma, soft

tissue injuries and long bone fractures. Therefore, in all the

cases, the etiological conditions for the fat embolism

occurrence were met. However, in none of the cases the

diagnosis was clinically established antemortem. The

examination by optic microscopy of the fragments of brain

and lungs collected during autopsy and stained with Sudan

III showed in all the cases the fat microemboli in the form of

orange globes disseminated throughout the fields examined

microscopically (figures 1-4) and allowed the postmortem

diagnosis of fat embolism. Therefore, in all three cases

presented, the results of the histopathological examination

of the fragments harvested from the brain and the lungs

during the autopsy were essential for determining the cause

of death.

Figure 1: Microscopic aspect of brain tissue

Sudan III stain x 40 (ice exam)

Figure 2: Microscopic aspect of lung tissue





59



DISCUSSION

Fat embolism occurs due to the mobilization of fat cells or

fat released by them, followed by their direct penetration

into open blood vessels or lymphatic channels. Most emboli

have a diameter of 15 to 40 μ; the fat emboli in the lungs are

generally larger than those in the large arteries of the

systemic circulation [11].

Several theories are mentioned in the literature to explain

the pathogenesis of the fat embolism [20].

The mechanical theory shows that mobilization of fat

particles occurs due to trauma to the bones or soft tissues.

As a consequence, the fat particles released by the trauma

enter the venous circulation from where they reach the

lungs, where the majority remains, but some of them can

also pass into the systemic circulation, reaching other

organs.

The biochemical theory, also known as the emulsion

instability theory, is mostly useful in explaining the non

traumatic fat embolism.

The intravascular coagulation theory holds that in stressing

conditions, substances that activate disseminated intra-

vascular coagulation and aggregation of fat particles are

released.

The toxic trauma theory claims that small blood vessels are

affected by high concentrations of fatty acids in the plasma

leading to increased vascular permeability.

The mechanical theory is based on the concept of the

mobilization of fatty bone marrow from the long bones

diaphysis. In the cases presented by us, only one patient

suffered a recent fracture of the femur. In the other two

cases we have to consider the trauma of soft tissues

(hypodermic tissue) as the cause of the fat embolism, by

noting that in both cases multiple ecchymoses were

observed on the skin.

From a clinical point of view, Gurd and Wilson have

developed the major and minor criteria which allow which

allow for the diagnosis of fat embolism. The major criteria

are: axillary or subconjunctival petechiae; hypoxaemia

(PaO2 <60 mm Hg, FIO2 = 0); central nervous system

depression disproportionate to hypoxaemia; pulmonary

oedema; radiological signs and symptoms of respiratory

insufficiency; cerebral changes unrelated to a cranial trauma

or other illness; rash. The minor criteria are: tachycardia

more than 110 bpm; pyrexia more than 38.5°C; fat globules

present in urine; changes in renal function (reduced urine

output); drop in haemoglobin level (more than 20% of the

value upon admission); drop in haematocrit values; drop in

platelet values (more than 50% of the value upon

admission); increased erythrocyte sedimentation rate

(greater than 71 mm per hour); fat globules present in the

sputum; emboli present in the retina; tachicardia; fever;

renal insufficiency; sudden thrombocytopenia. According to

Gurd and Wilson the diagnosis of fat embolism can be

established if either one major criterion and 4 minor criteria

or 2 major criteria are met [21].

Lindeque suggested that the criteria of Gurd and Wilson may

under-diagnose the syndrome, and proposed the following

criteria based on respiratory parameters: Pao2 kPa of less

than 8Fio2 0.21; Paco2 kPa or pH of less than 7.3 or more

than 7.3; respiratory rate greater than 35 breaths/min−1

even after adequate sedation; increased breathing efforts

showed by: dyspnea, use of accessory muscles, tachycardia

and anxiety [22]. Any patient with a fractured femur and/or

tibia, presenting one or more of these criteria, was

diagnosed with fat embolism syndrome. These criteria led to

the diagnosis of fat embolism syndrome in 29% of patients

in a series of 55, which is higher than other series, especially

since this study excludes patients with thoracic lesions,

where some of Lindeque's clinical signs may appear in the

absence of fat embolism [22].

Petechial eruption is considered a pathognomonic clinical

sign for fat embolism syndrome. It may occur in about 60%

of patients, usually on the conjunctiva, on the oral mucous

membrane and on the skin of the neck and shoulders. This

distribution can be explained by the drops of fat that

accumulate in the aortic arch before the independent

embolization at skin level through the subclavian and carotid

vessels [20, 23-25]. The factors contributing to the petechial

eruption are: stagnation of blood, loss of coagulation factors

and platelets, and damage to the endothelial walls due to

free fatty acids (FFA) leading to rupture of capillaries [25].

In the vast majority of cases, the fat embolism remains

asymptomatic, and the fat emboli are dispersed into small

cells and phagocyted by macrophages or embedded in

60

hepatic cells [26, 27]. Thus, many cases remain undiagnosed

before death.

In the three cases presented, the symptomatology before

death was poor and unspecific (febrile syndrome,

tachycardia, tachypnea), and remained undiagnosed. The

diagnosis of fat embolism syndrome was established only

after performing the autopsy, and the histopathological

examination of the brain and lung fragments stained

specifically with Sudan III. Therefore, for post mortem

diagnosis of fat embolism syndrome, it is essential to

perform a histopathological examination with special stains

that highlight the presence of fat emboli in the tissues and

organs.

In the cases presented in this paper, fat embolism at the

pulmonary and cerebral level was observed. According to

literature, brain and lung localizations are the most

important, although in most cases pulmonary fat embolism

remains clinically asymptomatic. In order to be able to certify

fat embolism as the cause of death, it is necessary for

histopathological examinations to find fat emboli on a large

part of the examination fields. The gravity of the

consequences of pulmonary embolism also depends on the

size and amount of fat emboli, as well as whether or not they

pass into the systemic circulation to the lung.

In the brain, emboli produce small petechial hemorrhages,

areas of ischemic necrosis and hemorrhage or necrosis and

demyelination. Cerebral embolism is considered in literature

as a paradoxical event, because it requires the presence of

cardiac atrial septal defects in order to be explained. In the

presented cases, there was no autopsy finding that showed

neither atrial or ventricular septal defects nor patent arterial

canal that could explain the cerebral fat embolism. An

explanation of the pathophysiological mechanism which

determined the cerebral embolism could not be found in this

study.

The cause of death in all the three cases presented in this

paper was the fat embolism. The diagnosis was established

with certainty only after autopsy, by a histopathological

examination which revealed the presence of fat emboli in

the lung and brain tissues. Of the cases presented only one

suffered a recent fracture of the femur; another presented

in addition to trauma paraclinical changes suggestive of

acute pancreatitis as a contributing factor; none had cardiac

malformations that could explain the paradoxical fat

embolism in the brain; all of the cases showed multiple

lesions of the subcutaneous tissue and death occurred

shortly after the initial trauma or after surgical interventions.

Death due to fat embolism can fall into the category of

violent or non-violent deaths. Regardless of the cause of fat

embolism, from forensic point of view the fat embolism is

considered a complication that leads to a secondary causal

relationship; in other words between the trauma/ initial

pathology and death an intermediate link is inserted

represented by a complication (the fat embolism) which is

connected to a greater or lesser extent to the initial trauma/

pathology [28-30].

CONCLUSION

From forensic point of view, the diagnostic certainty in

posttraumatic lesions is a priority objective. From the

diagnosis it is possible to reconstruct the thanatogenerator

mechanism and finally it can be useful to respond to the legal

aspects of the case, i.e. the causal relationship between

trauma and death.

In the case of trauma with reduced thanatogenerator

potential, which usually evolve without complications, the

occurrence of fat embolism syndrome followed by death

must be appropriately explained so that the case can be

properly framed from a legal point of view. It is important to

emphasize that the histopathological examination using

specific stainings, such as Sudan III, has a fundamental and

incontestable role in the diagnosis of fat embolism and in

estimating its gravity, and therefore, its implication in the

occurence of death.

Conflict of interest: The authors declare that there is no conflict of

interest.

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2. Taviloglu K, Yanar H. Fat embolism syndrome. Surgery today.

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lowering therapy: focus on the emerging drugs. Farmacia. 2014;

62(5):811-823.

4. Diaconu C, Bălăceanu A, Costache C. Prevalence of hypoxic

hepatitis in heart failure patients. J Hepatol. 2014; 60, Suppl 1: S515.

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European Association for the Study of Liver, April 9-13, 2014,

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Stanescu AM, Iancu MA, Scarneciu I, Zaha DC. Cross Sectional Study


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Regarding the Association between Sweetened Beverages Intake,

Fast-food Products, Body Mass Index, Fasting Blood Glucose and

Blood Pressure in the Young Adults from North-western Romania.

Rev Chim-Bucharest. 2019; 70(1):156-160.

6. Behn C, Höpker WW, Püschel K. Fat embolism-a too

infrequently determined pathoanatomic diagnosis.

Versicherungsmedizin. 1997; 49(3):89-93.

7. Hiss J, Kahana T, Kugel C. Beaten to death: why do they die? J

Trauma Acute Care Surg. 1996; 40(1):27-30.

8. Ioan B, Alexa T, Alexa ID. Do we still need the autopsy? Clinical

diagnosis versus autopsy diagnosis. Rom J Leg Med. 2012; 20(4):307-

312.

9. Roman G, Bala C, Creteanu G, Graur M, Morosanu M, Popa AR,

Pircalaboiu, L, Radulian G, Timar R, Cadariu AA. Obesity and health-

related lifestyle factors in the general population in Romania: a cross

sectional study. Acta Endo (Buc). 2015; 11(1):64-71.

10. Juncar M, Popa AR, Baciut MF, Juncar RI, Onisor-Gligor F, Bran

S, Baciut G. Evolution assessment of head and neck infections in

diabetic patients - A case control study. J Craniomaxillofac Surg.

2014; 42(5):498-502.

11. Chan KM, Tham KT, Chiu HS, Chow YN, Leung PC. Post-traumatic

fat embolism-its clinical and subclinical presentations. J Trauma.

1984; 24(1):45-49.

12. Velnic AA, Hanganu B, Petre-Ciudin V, Ioan BG. Clinical diagnosis

versus autopsy diagnosis in head trauma. Forensic Science

International. 2017; 277 (Suppl. 1): 209

13. Judea-Pusta CT, Muțiu G, Pașcalău AV, Buhaș CL, Ciursaș AN,

Nistor-Cseppento CD, Bodea A, Judea AS, Vicaș RM, Dobjanschi L,

Pop OL. The importance of the histopathological examination in

lethal acute intoxication with ethylene glycol. Case report. Rom J

Morphol Embryol. 2018; 59(3):965-969.

14. Pusta CT, Mihalache G, Buhas C, Pop O. A rare case of cardiac

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62


CLINICAL PRACTICE

Papillary thyroid carcinoma arising on a hypertrofic pyramidal lobe

Rodica Petris1, Ionut B. Sandu1, Adina Dragomir1, Dumitru Ioachim1, Cristina Iosif2, Ruxandra Dănciulescu-Miulescu3, Alexandra Mirica3, Diana Paun3

INTRODUCTION

Development of thyroid gland starts by the pharyngeal

epithelium thickening floor which later forms a diverticulum

which, in its development is pushed caudally. The descent

path is usually anterior to hyoid bone but it can also be

posterior or through the hyoid bone and ends on the

anterior surface of the first few tracheal rings.

This primitive steam that connects primordium with

pharyngeal floor becomes thyroglossal duct. Until the

second month of gestation thyroglossal duct devolve,

leaving at its place a small lump – the foramen cecum, at the

unification of third medium with posterior third of the

tongue, but portions of the duct associated with thyroid

tissue can persist at any site between tongue and thyroid [1,

2].

Cells in the lowest portion of the thyroglossal duct which

comprises normal thyroid tissue differentiates in forming

pyramidal lobe of the thyroid gland. Pyramidal lobe often

comes out from the thyroid isthmus, but can also come from

the medial side of one or both thyroid lobes [1]. The

pyramidal lobe is thought to be present in 15-75% of the

general population [1, 3]. Thyroglossal duct fails to involute

in approximately 7% of the population [4].

Many remnants of thyroglossal duct are never detected

clinically (2) and malignant transformation is uncommon [5].

CASE REPORT

We present the case of a 50 years old female patient with

chronic renal failure of unknown etiology (probably

secondary to hyper blood pressure), with Graves Disease (in

treatment with antithyroid drugs for about 1 year) who was

admitted in our department after she has initially presented

in an ENT department (Otolaryngology) for the investigation

of a tumoral mass located in the midline upper neck. At that

moment physical exam revealed a 2/3 cm mass between the

hyoid bone and the thyroid cartilage, mobile on swallowing,

painless spontaneously and on palpation, covered by normal

skin. IRM exam revealed a bilobate lesion 2.9/1.1 cm, very

well encountered, in close relationship with the adjacent

muscles and the hyoid bone, without any other pathological

changes on the structures of the anterior neck: no enlarged

lymph nodes. There were no reference about thyroid gland

on the IRM report. The IRM conclusion was: expansive

anterior cervical soft tissues tumoral mass. Surgical excision

of the tumoral mass and simultaneous removal of the central

portion of the hyoid bone (Sistrunk procedure) was

performed and the pathology report showed papillary

thyroid carcinoma arising from thyroglossal duct. In our

department, three months later, thyroid ultrasound showed

hypoechoic, inhomogeneous echotexture suggestive for

chronic autoimmune process, hypoechoic nodule with

discrete Doppler flow, without hypoechoic halo located at

the connection of the right thyroid lobe with isthmus and

two micro lymph nodes with intense Doppler flow, without

hilum of 0.5/0.4 cm and 0.7/0.4 cm located anterior of the

larynx. Tumoral mass previously removed in the ENT

department was reviewed and the pathology report showed

tumoral multilobulated pyramidal thyroid lobe with pattern

1 C.I. Parhon National Institute of Endocrinology, Bucharest, Romania 2 St Maria General Hospital, Bucharest, Romania 3 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania


63

of solid and sclerosant variant of papillary carcinoma,

infiltrative into fibro conjunctive, adipose and muscular

adjacent tissue (Figure 1 and Figure 2) and areas of micro

angioinvasion of the capsule (Figure 3).

Figure 1: Papillary carcinoma infiltrative into fibroconjunctive,

adipos and muscular adjacent tissue (x20 HE)

Figure 2: Papillary carcinoma infiltrative into fibroconjunctive

adipose and muscular adjacent tissue (x40 HE)

Figure 3: Micro invasion of the capsule (x200 HE)

In this context, we decided total thyroidectomy (also as a

treatment for Graves Disease) with dissection of central

lymph nodes compartment. Histopathology report revealed

embedded thyroid isthmus focus of papillary thyroid

carcinoma 0.7/0.6 cm with tumoral pattern similar to that of

tumoral pyramidal lobe previously removed (Figure 4), with

areas of marginal invasion of the capsule (Figure 5) and

micro angioinvasion of the capsule (Figure 6). The pathology

report also showed reactive lymphadenopathy and post

surgery staging was pT3N0.

Figure 4: Embedded thyroid isthmus focus of papillary thyroid

carcinoma (x20 HE)

Figure 5: Marginal invasion of the capsule (x100 HE)

Figure 6: Microangioinvasion of the capsule (x100 HE)

Radioactive iodine therapy was decided. Postsurgery,

thyroglobulin level after Levothyroxine withdrawal is 0.2

ng/ml with unmeasurable thyroglobulin antibodies and 50

mCi 131I was administered. Post ablation thyroid scan

showed no uptake of 131I in the thyroid bed or elsewhere in

the body. Because of the association of BRAF mutation with

papillary carcinoma of the pyramidal thyroid lobe, genetic

testing of BRAF gene were performed and they were

negative for somatic mutations in the 600 codon.

DISCUSSION

The detection of a pyramidal lobe or a thyroglossal duct in

patients with hyperthyroidism is indicative of autoimmune

64

hyperthyroidism. The vestiges of thyroglossal tract are more

often seen in patients with Graves Disease compared with

patients with autonomously functioning thyroid nodules and

this is related with the presence of stimulating thyrotropin

receptor antibodies [6, 7]. Pyramidal lobe can be the primary

or secondary site of thyroid malignancy and during

thyroidectomy, total excision of the pyramidal lobe is

essential for patients with thyroid cancers who undergo

radioactive iodine treatment (RAI) because the presence of

pyramidal lobe prevents the increase in TSH and absorbs a

large amount of the isotope and thus decrease the possibility

to benefit from the treatment [8-10]. Residual pyramidal

lobe can harbor cancer cells and from this point of view its

total excision is indicated in thyroid cancers. In case of

probable recurrence of malignant diseases due to pyramidal

remnants, scintigraphy, ultrasound of the neck, computed

tomography are indicated [11-13]

Thyroid pyramidal lobe can be the origin or recurrent site of

papillary thyroid carcinoma. Malignant tumors arising from

pyramidal lobe are rare and are associated with a high rate

of concurrent thyroid cancer and it must be differentiated

from thyroglossal papillary cancers because pyramidal

cancer requires orthostatic thyroid surgery which is not

always necessary in papillary thyroglossal cancers [14, 15].

Pyramidal lobe tumors are associated with poor prognostic

factors such as: extra thyroidal extension, advanced T-stage,

cervical lymph node metastasis, advanced AJCC stage (III, IV),

BRAF mutation, multifocal thyroid cancer [16, 17]. In our

patient there was one single embedded thyroid focus, no

local lymph nodes metastasis and no distant metastasis.

BRAF mutation was negative.

Malignant tumors arising from thyroglossal duct are also

rare [18]. The majority are papillary carcinomas (about 94%)

and less than 5% are squamous carcinoma [19]. The Sistrunk

procedure that implies the simultaneous removal of the

central portion of the hyoid bone to ensure the complete

removal of the thyroglossal tract is enough for thyroglossal

squamous carcinoma although they have a poor prognosis

and a mortality rate of 30-40% [20]. On the other hand,

papillary thyroglossal carcinomas are multicentric and

multifocal and total thyroidectomy followed by 131I ablation

and thyroid-stimulating hormone suppression is often

required. There are still controversy regarding the need for

total thyroidectomy, central or lateral compartment neck

dissection and I131 ablation therapy in cases of papillary

carcinoma of thyroglossal duct [21]. The decision depends

on: tumor size (tumors larger than 1 cm require total

thyroidectomy), abnormal findings of thyroid (multinodular

goiter, cold nodule in a thyroid iodine uptake), histopa-

thological findings, and the presence of enlarged lymph

nodes or a history of neck irradiation [22].

In conclusion: in this report we have described a papillary

thyroid carcinoma arising from a multilobulated pyramidal

lobe including from a nodular peri-isthmic remnant of the

pyramidal lobe (secondary to incompletely resected anterior

tumor of the isthmus), in a patient with Graves Disease. The

rest of the thyroid parenchyma is non tumoral. The complete

resection of the thyroid is necessary because of tumor

aggressiveness and the necessity of radioiodine ablation

therapy.

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32-35.

13. Zivic, R., et al., Surgical anatomy of the pyramidal lobe and its

significance in thyroid surgery. S Afr J Surg, 2011. 49(3): p. 110, 112,

114 passim.

14. Machens, A., H.J. Holzhausen, and H. Dralle, The prognostic

value of primary tumor size in papillary and follicular thyroid

carcinoma. Cancer, 2005. 103(11): p. 2269-2273.

15. Witt, R.L., Initial surgical management of thyroid cancer. Surg

Oncol Clin N Am, 2008. 17(1): p. 71-91, viii.

16. Ogawa, C., et al., Follicular carcinoma arising from the pyramidal

lobe of the thyroid. J Nippon Med Sch, 2009. 76(3): p. 169-172.

17. Lee, Y.S., et al., Recurrence of papillary thyroid carcinoma in a

remnant pyramidal lobe. ANZ J Surg, 2011. 81(4): p. 304.

18. Weiss, S.D. and C.C. Orlich, Primary papillary carcinoma of a

thyroglossal duct cyst: report of a case and literature review. Br J

Surg, 1991. 78(1): p. 87-89.

19. Wexler, M.J., Surgical management of thyroglossal duct

carcinoma: is an aggressive approach justified? Can J Surg, 1996.

39(4): p. 263-264.

20. Boswell, W.C., et al., Thyroglossal duct carcinoma. Am Surg,

1994. 60(9): p. 650-655.

21. Dedivitis, R.A. and A.V. Guimaraes, Papillary thyroid carcinoma

in thyroglossal duct cyst. Int Surg, 2000. 85(3): p. 198-201.

22. Kazemi, M., et al., Primary papillary carcinoma in a thyroglossal

duct cyst. Hell J Nucl Med, 2006. 9(1): p. 39-40.

66

Article received on March 11, 2019 and accepted for publishing on May 13, 2019.

CLINICAL PRACTICE

Atypical Cogan syndrome; case report

Gabriela C. Musat1,2, Roxana E. Decusara2, Ovidiu Musat3

Abstract: Cogan syndrome is a rare disease characterized by the concomitance of non-syphilitic interstitial keratitis with Meniere-like vestibulo-auditory symptoms. There are criteria for the diagnosis of both typical and atypical Cogan syndrome. We present the case of a 40 years old woman with sudden onset of hearing loss, tinnitus, intense vertigo, instability associated with kerato-conjunctivitis. The concomitance of the symptoms, the onset, and the evolution under treatment are consistent with the diagnosis of atypical Cogan syndrome.

Keywords: Cogan syndrome, atypical Cogan syndrome; vertigo; hearing loss

INTRODUCTION

Cogan syndrome is a disorder characterized by the

association between the Meniere-like vestibulo-auditory

symptoms and ocular symptoms (interstitial keratitis).

Although the first to describe a disorder associating ocular

and inner ear symptoms were Morgan RF, Baumgartner in

1934 [1], the name of the disease comes from Dr. David

Cogan who published in 1945 a series of 4 cases of patients

with non syphilitic interstitial keratitis and vestibulo-

auditory symptoms [2]. In 1980 Haynes et al proposed the

enlargement of the criteria for the diagnosis, defining typical

and atypical Cogan syndrome. They proposed that other

ophthalmologic inflammatory manifestations such as

episcleritis, uveitis, conjunctivitis, can be considered as

disease criteria for atypical syndrome. [3]

For a disease described such a long time ago there is very

little knowledge about the etiology of the disorder. Until

now, approximately 250 cases have been published but we

still don’t understand the etiopathogeny of the disease. It is

considered an autoimmune disorder. This disease seems to

affect young Caucasian adults with ages ranging between 25

to 35 years old, in most of the cases. [5]

CLINICAL FEATURES

Ocular manifestations: The main characteristic of the

disease is the ocular involvement. Usually patients have red

eye, eye pain and photophobia. The typical Cogan syndrome

is defined by the presence of the non syphilitic interstitial

keratitis. The examiner might notice granular and irregular

infiltrate on the posterior part of the cornea.

Neovascularization is also a possibility. Blindness and

amaurisis can happen but usually the lesion regresses and

the loss of visual acuity is moderate. In the majority of the

cases both eyes are affected, the unilateral disease is

infrequent [6]. In the atypical Cogan syndrome the vestibulo-

cochlear manifestations can be associated with scleritis,

episceritis, uveitis, optic neuritis, conjunctivitis or glaucoma.

[7]

Vestibulo-cochlear symptoms: Cogan syndrome is classically

characterized by sensory-neural hearing loss, vertigo and

1 St Maria General Hospital, Bucharest, Romania 2 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 3 Carol Davila University Emergency Central Military Hospital, Bucharest, Romania


67

tinnitus in an association that resembles to Meniere’s

disease. The hearing loss might be profound, leading to

cophosis in almost 52% of cases and usually it is bilateral. The

auditory deficit is installed in days, months, too slow for a

sudden nerosensorial hearing loss and too quick for a

presbyacusys. The speech discrimination scores are poor.

The hearing loss is associated with tinnitus. [4]

The vertigo can be important causing marked instability,

ataxia, sometimes associated with nausea and vomiting. The

nystagmus can be observed at the ocular examination. In

most of the cases, complains are similar to Meniere’s

disease.

Other signs and symptoms

General manifestations of the disease are not rare, fever has

been reported in many cases, weight loss and extreme

asthenia can be found in patients with Cogan’s.

Cardiac involvement, especially aortic insufficiency is

present in as much as 15% of cases. Large vessels can also be

affected causing heart murmur, abdominal pain,

claudication of the members.

Musculo-scheletal involvement manifests as myalgia or

arthritis (mono, oligo or polyarthritis).

Neurological signs appear in ¼ of cases [8], patients might

have paresis, hemiplegia, aphasia, cerebellar syndrome,

pyramidal syndrome, spinal cord disorders, epilepsy, and

vigilance disorders. MRI can sometimes detect lesions of the

white matter consistent with cerebral vasculitis.

Cutaneous lesions might appear during attacks taking the

form of urticarial rash, vascular purpura, ulcerations or

nodules.

Some patients might have gastro-intestinal or pulmonary

symptoms.

Laboratory investigations

Biologic parameters can be modified in Cogan syndrome,

especially during the attacks, but no laboratory test in

pathognomonic for the disease. Leukocytosis, elevated ESR,

anemia, hyperfibrinemia may appear. Several immune-

logical modifications also can be noticed: rheumatoid factor,

antinuclear antibodies, cryoglobulins, lupus anticoagulant

but none of these are specific or relevant for the disease. [9]

In small series of patients, some authors determined the

presence of specific antibodies for the inner ear or cornea

but these studies were not relevant and could not be

reproduced by other authors so cannot be used to support

the diagnosis of Cogan.

Differential diagnosis

The first differential diagnosis one should bear in mind when

facing a rapid onset hearing loss with vestibular symptoms

and interstitial keratitis is syphilis. Another important

differential diagnosis is Meniere’s disease but in this case the

ocular manifestations are absent.

Another diagnosis to be differentiated from Cogan is Susac

syndrome, a retino-cochleo-cerebral vasculopathy involving

the arterioles, manifested by central neurological disorders,

visual acuity loss, and hearing loss.[10] Vogt- Koyanagi-

Harada syndrome is characterized by uveitis, alopecia,

vitiligo and audio-vestibular symptoms.[11] . Other systemic

diseases such as Wegener granulomatosis, PAN, relapsing

polychondritis, Behcet disease, and Sjogren syndrome can

associate vestibulo-auditory symptoms with ocular

involvement.

Evolution, prognosis

In some cases, the onset of the disease is preceded by upper

respiratory tract viral infection.

The vestibular and auditory symptoms can be the first

manifestations of the disease in 41% of cases. in 43 % of

cases the Cogan syndrome debuts with the ocular

symptoms. The involvement of the two organs is usually

done in approximately 3 months [8]. In cases of atypical

Cogan syndrome the complete symptomatology might be

installed in a long period, even years.

Usually, after the first attack the disease enters a phase of

remission without evident symptomatology. There is a

possibility that there are recurrent episodes that repeat at

variable intervals. Once installed the hearing loss is not

remissible. The vestibular symptoms diminish as a result of

the compensation mechanisms. The ocular symptoms have

a variable evolution, but usually respond favorably to

treatment.

Treatment

As the etiology and the pathogenic mechanisms are not

known, there is not yet available a codified treatment for

Cogan’s syndrome.

Usually the first line of treatment is represented by

corticosteroids. [12] In cases where the corticodependence

is installed or in cases of corticoresistance there is the

possibility of using other therapeutic agents such as

immunosupressants (cyclophosphamide, azathioprine, and

methotrexate). [13] The corticotherapy should be prescribed

in high dosage (1-1.5 mg prednisone or equivalent) and

interrupted in two weeks in cases where it is ineffective.

Studies show that the vestibulo-cochlear symptoms respond

68

to treatment only in one third of the cases (orphanet). Once

the deafness is installed, it is usually non-reversible.

In the last years there were attempts to treat Cogan

syndrome with TNF alfa blockers but there are not enough

evidence based results [14, 15]

CASE REPORT

We present the case of a 40 years old woman with no

remarkable medical history who presented at the

emergency department of our hospital accusing sudden

onset intense vertigo and dizziness, tinnitus and hearing loss

in the right ear. The patient was admitted in the ENT

department.

The physical examination of the patient yielded no relevant

data, the ENT exam was within normal limits.

The vestibular examination pointed out to an important

instability, the patient was unable to maintain orthostatic

position or walk without support, no spontaneous

nystagmus.

The cerebral IRM examination did not reveal any vascular or

tumoral lesions. The neurologic examination did not

discover any motor or sensorial deficit, no signs of

localization.

The audiogram performed initially can be visualized in Figure

1. We diagnosed a profound sensoryneural hearing loss for

the right ear and a medium sensory-neural hearing loss for

the left ear.

Figure 1: Initial audiogram

The rheumatologic examination revealed no remarkable

findings: no arthritis, no cutaneous lesions, and no ocular

symptoms.

The blood hematological and biochemical parameters were

modified showing a slight leukocytosis with a white blood

count of 11000/mm3, the ESR also slightly elevated 25

mm/hour and the CRP had the value of 5. The modifications

were interpreted as a reaction to an acute dental infection

the patient had at that moment.

All the immunologic tests we performed were in normal

limits, IgA, IgG, IgM, ANA, antibodies anti beta 2

glycoprotein, antibodies antiphospholipid were tested and

the values were normal. Antibodies Ig M and Ig G for Epstein

Bar virus, Toxoplasma, HIV, herpes virus, cytomegalovirus

were all negative.

The ophthalmologic examination did not find any

modifications of the anterior ocular pole at that initial

moment.

The computerized posturography we performed at

admission showed a severe vestibular deficiency pattern

(Figure 2).

The videonystagmography with caloric testing evidenced a

total right areflexia and an extremely important left

hyporeflexia (Figure 3).

We started a treatment with high dose corticotherapy (solu-

medrol), antiemetic (osetron), vestibular suppressant

(diazepam), vasoactive agent (pentoxyphilin), vitamin (B1

and B6), plasma expander(dextran 40).

During the treatment, the patient presented a fluctuating

evolution. The hearing level fluctuated especially on the left

ear with PTA between 30 and 60 and on the right ear with

PTA between 60 to 90.

In Figure 4 it can be noticed the aspect of two audiograms

we performed during the treatment in which we could

observe the fluctuant hypoaccusis in both ears.

The dizziness also fluctuated with episodes of severe vertigo.

In these episodes, the direction of the nystagmus varied. We

recorded horizontal rotatory nystagmus beating to the left

but also to the right (Figure 5) alternating with periods of lack


69

of nystagmus.

Figure 2: Computerized posturography

Figure 3: Videonystagmography

Figure 4: Audiograms during the treatment

70

Figure 5: Horizontal rotatory nystagmus beating to the left but also to the right, alternating with periods of lack of nystagmus

After 10 days of treatment in the hospital, the patient was

discharged with an improvement of the hearing loss in the

left ear, no vertigo and only a mild dizziness.

One month after this episode, the patient presented once

again at the emergency department accusing intense

vertigo, nausea, vomiting, tinnitus and aural fullness in the

left ear. The audiogram evidenced a bilateral severe hearing

loss (Figure 6).

Figure 6: Bilateral severe hearing loss

The rheumatologic examination did not reveal any

modifications. The second day of hospitalization the patient

suddenly presented eye pain with intense redness of the

conjunctive. The ophthalmologic examination established

the diagnosis of kerato-conjunctivitis (Figure 7).

In this moment, we were able to diagnose an atypical Cogan

syndrome taking into account the association between the

audio-vestibular symptoms with an inflammatory ocular

disease.

We repeated the same treatment as in the first episode

associating local eye topical corticosteroids and artificial tear

solution with a major improvement of the hearing loss for

the left ear PTA 10 (Figure 8).

The patient was discharged with a prescription of

prednisone in low dose for a period of three months.

One year later, in the follow up, we noticed that the hearing

in the right ear did not improve at all but the instability

improved a lot so the patient was able to continue with

everyday life. In this year she did not have any attack, no

audiovestibular or ocular symptoms.

DISCUSSION

Haynes et al described atypical Cogan syndrome for the first

time in 1980. The typical Cogan syndrome was described as

an association between Meniere–like audio-vestibulary

symptoms and non-syphilitic interstitial keratitis with an


71

interval between the onsets of the symptoms of less than

two years.

Figure 7: Kerato-conjunctivitis

The atypical Cogan syndrome consists in an association of

symptoms in which the disease criteria are grouped as

follows:

• Inflammatory ocular manifestations with or without

interstitial keratitis

• Typical ocular manifestations associated with audio-

vestibular symptoms different from Meniere’s

• A delay of more than 2 years between the onset of typical

ocular and audio-vestibular manifestations.

The atypical Cogan syndrome with ocular manifestations

other than interstitial keratitis tends to have a higher rate of

systemic involvement with aortitis and has a worse

prognosis. [3, 16]

It is the case of a 40-year-old woman with acute onset of

intense audio-vestibulary symptoms with no remarkable

medical history and no other general manifestations. At the

first presentation the diagnosis of presumption was Meniere

disease but there were characteristics of the evolution that

did not entirely correspond. The disease was rapidly onset

with bilateral and unequal involvement. The right ear had a

profound hearing loss from the very beginning and

practically did not respond to treatment. The left ear had a

minor amelioration in the first episode and quite a good

response in the second episode of the disease although the

treatment was similar. During the admission we performed

multiple audiograms evidencing the fact that the thresholds

at both ears were in a continuous modification, not

respecting the classical pattern of Meniere’s. The

videonystagmography with calorics showing bilateral

vestibular lesion from the beginning of the disease, was also

atypical for Meniere.

Figure 8: Major improvement of the hearing loss for the left ear

The onset and evolution of the disease made us believe that

there is a autoimmune disorder of the inner ear but we did

not have any disease criteria to classify. The laboratory tests

were within normal limits, the minor leukocytosis and the

slight elevated ESR were not noticeable. No other

immunologic tests were modified or virus infections

detected.

At the second episode of disease, the concomitance with the

kerato-conjunctivitis was consistent with the diagnosis of

atypical Cogan syndrome. We consider that this is the only

disorder that can be taken into account for the diagnosis of

this patient. Another remark is the fact that the patient is

over the age of typical onset of the disease, but there are

many reports of atypical Cogan with patients in the same age

group. [17, 18]

The response to corticotherapy, was partial as the right ear

did not recover, but the final result was considered

satisfactory by the patient who could continue her daily

activities.

72

CONCLUSION

Although Cogan syndrome is a rare disease, we must bear in

mind that there is always a possibility of diagnosing it in the

case of a patient with both vestibule-auditory symptoms and

ocular manifestations.

Typical and atypical Cogan syndrome are diagnosed mainly

based on clinical criteria as there are no laboratory tests able

to evidentiate the disease.

The treatment consists mainly in corticotherapy. Immuno-

suppressants are an option in cases where corticotherapy is

inefficient.

References:

1. Morgan RF, Baumgartner CJ. Ménière’s disease complicated by

recurrent interstitial keratitis: excellent result following cervical

ganglionectomy. West J Surg 1934;42:628-31.

2. Cogan DG. Syndrome of nonsyphilitic interstitial keratitis and

vestibule-auditory symptoms. Arch Ophthalmol 1945;33:144-9.

3. Haynes BF, Kaiser-Kupfer MI, mason P, Fauci AS. Cogan

syndrome studies in thirteen patients, long term follow-up, and

review of the literature Medicine.1980 69426-41

4. M. B. Gluth, K. H. Baratz, E. L. Matteson, and C. L. W. Driscoll,

“Cogan syndrome: a retrospective review of 60 patients throughout

a half century,” Mayo Clinic Proceedings, vol. 81, no. 4, pp. 483–488,

2006

5. J. Cundiff, S. Kansal, A. Kumar, D. A. Goldstein, and H. H. Tessler,

“Cogan's syndrome: a cause of progressive hearing deafness,” The

American Journal of Otolaryngology, vol. 27, no. 1, pp. 68–70, 2006

6. R. M. McCallum and B. F. Haynes, “Cogan's syndrome,” in Ocular

Infection & Immunity, J. S. Pepose, G. N. Holland, and K. R.

Wilhelmus, Eds., p. 446, Mosby, St. Louis, Miss, USA, 1st edition,

1996

7. A. Grasland, J. Pouchot, E. Hachulla, O. Bletry, T. Papo, and P.

Vinceneux, “Typical and atypical Cogan’s syndrome: 32 cases and

review of literature,” Rheumatology, vol. 43, pp. 1007–1015, 2004

8. P. Vinceneux, Cogan Syndrome, Orphanet Encyclopedia, 2005

9. R. S. Vollertsen, T. J. McDonald, B. R. Younge et al., “Cogan's

syndrome: 18 cases and a review of the literature,” Mayo Clinic

Proceedings, vol. 61, no. 5, pp. 344–361, 1986.

10. Kleffner I, Dörr J, Ringelstein M for the European Susac

Consortium (EuSaC), et al Diagnostic criteria for Susac syndromeJ

Neurol Neurosurg Psychiatry;87:1287-129. 2016

11. Andreoli CM, Foster CS. Vogt-Koyanagi-Harada disease. Int

Ophthalmol Clin. Spring. 46(2):111-22. 2006

12. E. W. St. Clair and R. M. McCallum, “Cogan's syndrome,” Current

Opinion in Rheumatology, vol. 11, no. 1, pp. 47–52, 1999

13. L. Riente, E. Taglione, and S. Berrettini, “Efficacy of

methotrexate in Cogan's syndrome,” Journal of Rheumatology, vol.

23, no. 10, pp. 1830–1831, 1996

14. Z. Touma, R. Nawwar, U. Hadi, M. Hourani, and T. Arayssi, “The

use of TNF-α blockers in Cogan's syndrome,” Rheumatology

International, vol. 27, no. 10, pp. 995–996, 2007.

15. M. Fricker, A. Baumann, F. Wermelinger, P. M. Villiger, and A.

Helbling, “A novel therapeutic option in Cogan diseases? TNF-α

blockers,” Rheumatology International, vol. 27, no. 5, pp. 493–495,

2007.

16. João Queirós, Sofia Maia, Mariana Seca, António Friande, Maria

Araújo, and Angelina Meireles, “Atypical Cogan's Syndrome,” Case

Reports in Ophthalmological Medicine” 2013

17. Cogan's syndrome--an interdisciplinary diagnostic challenge.

Lyhne NM, Mortensen MV. Ugeskr Laeger. 173(40):2503-4) 2011

18. Ying YL, Hirsch BE. Atypical Cogan's syndrome: a case report. Am

JOtolaryngol. Jul-Aug;31(4):279-82. 2010


73


VARIA

Patient-physician communication, an essential condition for an effective medical act

Carmen M. Voicu1, Consuela M. Gheorghe1

An inconceivable reality for the medical world today is to

consider the patient an active factor in his own healing

process. Placement of the patient in the center of healthcare

services aims at his loyalty, which means creating and

maintaining correct and long-lasting relationships with him.

In addition, in order to create such relationships with

patients, both loyalty and stability, performance, and

profitability strategies of the medical team must be thought

on long-term.

Healthcare marketing situations differ, and medical units

concerned with the essence of success must strive for a

strategic alignment of relationships between all

stakeholders (decision-makers, medical staff, patients, etc.)

and the power of these relationships to improve their

mutual value and even the relational context as a whole,

turning patients into true brand promoters, thus enhancing

marketing efforts [1].

The patient reaches to attitudes, judgements, and

preferences about certain brands through a procedure of

evaluating the features of these brands, developing a set of

beliefs about the features that correspond to each brand [2].

Recognition of the strategic relationship that a patient

desires is a medical marketing reality and involves greater

commitment to accepting the challenge of creative thinking

in often difficult situations, progressing through knowledge

and understanding to mutual trust, converting emotions into

balanced normality and the relationship thus created into an

emotional-connected and loyal one for a certain period of

time. This means concentrating efforts on patients,

attention, and receptiveness to his wishes, but

professionalism and rigor in such a way that his personal

health expectations are not in vain. Moreover, it is very

important to pay a close attention to communicating with

him; it is even said that this type of communication is the

broker of the relationship developed in a sensitive and

dynamic environment like the healthcare field.

The complexity of providing healthcare services, on the one

hand, and the wishes and expectations of patients, on the

other hand, have as result special patient-physician

communication valences and turn it into an essential

condition. Permanent and effective communication with

patients has become a condition of the existence of a

qualitative medical act.

Given the continuous increase and diversification of health

services, communication issues are becoming increasingly

difficult and require much more laborious information

efforts.

Due to the information explosion, patients tend to

appreciate the quality of a product or service based on

perceptions rather than on reality.

That is why efforts to optimize the technological and

informational processes of communication between

patients and medical staff, of exploring patients’ behaviors

regarding interpersonal communication in electronic

environments in health services, of modeling negative

emotions, of ways of transforming the healthcare

infrastructure so that it offers an integrated insight of

information through the optimized clinical and business

processes, of welfare and health management, of patient-

centered networks, of investigating the influence of virtual

communities on the reputations of health organizations in

Romania, has become a permanent necessity [3].

74

The relationship between the two sides, medical staff-

patient, in the healthcare field, is much more complex,

addressing social, psychological, and cultural aspects, which

besides the base of the therapeutic level also implies a

superior level of existential communication. The latter is

found in medical communication because the medical act

interferes with the destiny of the patient, linked in turn with

elements of uncertainty and individual instability [4].

Interpersonal communication was the first spiritual

instrument of the human being in the process of socializing,

and is defined as the communication that occurs between

two people in the context of their relationship and which, as

it evolves, helps them negotiate and define the relationship

[5].

Communication within the health organization takes place in

a complex environment, where continuously modifying

favorable and unfavorable factors coexist. Communication

can take many forms and can be seen in different situations,

but the most important of these is undoubtedly between

patient and physician, which provide much of the data

needed to establish the diagnosis and therapeutic attitude.

Interpersonal communication is formed by the combination

of verbal forms (oral and written), nonverbal forms

(gestures, mimics, posture, movement, aspect) and

paraverbal forms (by voice attributes accompanying the

word, such as intonation, rhythm, verbal flow), but,

considering the importance of the information content of

patient-physician communication (the diagnosis and

treatment process), in the medical system, the emphasis is

more on verbal communication. Non-verbal and paraverbal

forms are important from the point of view of their

emotional effect and the formation of sympathy.

In the health system, the relationship between the two sides,

the medical staff-patient, is much more complex, involving a

higher-level therapeutic type of existential communication.

This type of communication [4] is involved in medical

communication, because the medical act interferes with the

destiny and evolution of the patient, being in turn linked to

elements of uncertainty and individual instability.

On the other hand, the position of the two entities, namely

the medical staff-patient, is different and unequal [6]. This

relationship is established between members of two distinct

social groups in terms of their prestige, power, and

orientations. Thus, the physician has an extremely high

status, given the level of information held and the

specialized guidance through which he exercises his full

authority.

The social role of the patient demonstrates his vulnerability,

being forced to seek support whenever he needs. Thus, the

patient is the most disadvantaged person, being influenced

by physical and mental suffering, feeling the disease as a

source of uncertainty and insecurity, while the physician is

regarded as a person with multiple qualities, full of energy

and sometimes with magical powers.

Gaining a high communicative competency needed by the

specialist to create a real therapeutic alliance requires not

only solid medical knowledge to diagnose and treat the

disease but also the ability to obtain as much information as

possible from the patient and interpersonal skills to respond

to feelings and patient concerns and the ability to create and

maintain the therapeutic relationship as a concrete offer of

information and medical education [7].

Health communication is “the study and use of

communication strategies to inform and influence the

choices people make regarding their health”, and health

information technology includes “digital instruments and

services used to enhance self-care of patients, assisting

patient-provider communication, informing about health

behaviors, preventing health complications and promoting

equity in health” [8].

A major concern of health services and primarily of hospitals

has become communicating with patients, the quality of

information provided to patients by physicians and the rest

of the medical team. An essential component is the

transmission of information, which has become increasingly

important in medical deontology. This development is

primarily driven by wishes of patients, more trained in health

issues, and more cautious about the quality of the

explanations they are given.

In the hospital environment, where the patient is subject to

the attention of medical teams, the coherence of “what is

said and what is not” becomes a permanent goal for patients

and their relatives. Because, beyond anything “...there is an

informational asymmetry between the physician and the

patient: when they find themselves in the hospital (...), they

feel ill, they do not feel what is going on with them, they do

not know the possibilities of medical science, so they

empower the physician with the freedom of choice” [9]. A

good professional behavior is to state exactly how we are

feeling and to write what we are saying. However, each

physician is the supreme judge of how he or she does and

can enrich his or her oral information by using information

charts and, if considered necessary, by other documents or

video support.

In healthcare services, access to online information has

made patients more aware of their needs and desires so the

result has materialized in a rigorous selection of service


75

providers.

Therefore, healthcare managers and providers need to

understand the stages a potential patient is going through in

an online buying process or when expressing an intention to

buy an online health product or service.

The winners will be those who build trust from the patient’s

perspective, with three progressive complex components in

the relationship between the brand and him: credibility,

care, and congruence. Certainly, what is very important is

the amount of money spent by the patient for the recovery

of health.

Nowadays, in health systems, the widened marketing mix

enjoys considerable attention. It provides a simple

organizational mechanism to understand the problems

arising from the concerns of medical service providers. The

widened mix has also developed as a partial solution to some

of the most important problems faced by managers in terms

of quality control of healthcare services provided and the

relationship with patients in the process of providing these

services. The widened mix explicitly recognizes the role of

the staff and patients in the service delivery process,

highlighting the role of marketing played by both sides.

The inclusion of Physical Evidence, Participants, and Process

as distinct (contextual) elements underlines their

importance and impact on marketing of health services. In

addition, the key objectives are to increase patient

satisfaction, quality of medical services offered and long-

term patient gaining, which means that the widened

marketing mix management is directly related to these

objectives.

Due to the immaterial nature of healthcare service and the

fact that, usually, they cannot be checked beforehand,

patients are looking for tangible evidence of what they are

about to experience in a particular immediate confrontation

with the medical service. Even if a patient has a high

experience with such a healthcare provider, variations, and

contextual elements will affect patient’s expectations

related to the immediate confrontation with a medical

service.

Elements of “Physical Evidence”, such as noise level, smell,

temperature, time, comfort, and even nutrition, will

influence the perceptions of confronting with the healthcare

service requested. Similarly, the attitudes and behavior of

healthcare participants will influence the perceptions of

current performance. Contextual elements can also

influence satisfaction in the confrontation with the medical

service, through their effects on attributions (of causes) for

invalidation. Theory of attribution asserts that when results

are not in line with expectations, people tend to look for

reasons. The importance they give to “why”, will influence

the final evaluation of the outcome.

The communication process is very important within the

medical unit; it is a process that affects the quality of the

other processes. Through the positive impact on

communication within the medical unit, the style oriented

towards maintaining socio-emotional aspects and the

leadership style oriented towards relationships is beneficial

to the processes within the medical unit and to the

emergence of positive socio-emotional states. This

leadership style is associated with the existence of high

quality communication relationships, which leads to the

improvement of the quality of the other processes [10].

In the new context of health, development processes will

need to focus not only on solving current problems, but also

on anticipating future problems, not just on certain types of

processes, but as many as possible, not just on technical

resources, but more on human ones. Organizational-

managerial excellence seeks not just the adaptation to

circumstances, but also the becoming and the power to

create the circumstances [11].

The depth of the process of change in health, its size, and its

dynamics depend not only on the political will and on the

subjective aspirations, but also on the existence and

sufficiency of the necessary objective conditions, the

managerial ones being the first.

In the context of today’s healthcare problems, the special

role of the manager is imposed by the need to create a

general capacity for innovation, flexibility, stability, and

ensuring success even in extreme situations. In this context,

the theoretical but especially the methodological approach

of the marketing of the medical system has special practical

valences, requiring a change in the mental attitude of health

managers towards an innovative strategic hospital

marketing oriented towards and for the benefit of patients

[12].

References:

1. Batterley R. Leading Through Relationship Marketing. 2004,

McGraw-Hill Australia Pty Ltd.

2. Kotler P, Shalowitz J, Stevens RJ. Strategic marketing for Health

Care Organizations - Building a Customer – Driven Health System.

2008, Jossey Bass A Wiley Imprint.

76

3. Purcarea VL. Impactul tehnologiilor informationale asupra

sistemului de sanatate. Teza de abilitare, 2013.

4. Cosman D. Psihologie medicală. 2010, Iaşi, Editura Polirom.

5. Floyd K. Comunicarea interpersonală. 2013, Iaşi, Editura

Polirom.

6. Chichirez CM, Purcărea VL. Interpersonal Communication in

Healthcare. Journal of Medicine and Life. April-June 2018;

11(2):119-122.

7. Servellen van GM. Communication skills for the health care

professional: Concepts, practice, and evidence. 2009, Canada, Jones

& Barrlett Publishers.

8. https://www.healthypeople.gov/2020/topics-objectives/

topic/health-communication-and-health-information-technology.

9. de Kervasdoné J. La generalité de soin on France. 2000, 46.

10. Curşeu PL, Schalk MJD, Wessel I. How do virtual teams process

information?. A literature review and implications for management.

Journal of Managerial Psychology. 2008; 23,6,628-652.

11. Ciurea AV, Ciubotaru VG, Avram E. Dezvoltarea

managementului în organizaţiile sănătăţii. Excelenţa în serviciile de

neurochirurgie. 2007, Bucureşti, Editura Universitară.

12. Popa F, Purcarea Th, Purcarea VL, Ratiu M. Marketingul

serviciilor de ingrijire a sanatatii. 2007, Bucuresti, Ed. Universitara

”Carol Davila”.


77


VARIA

The tree we throw stones at

Mihail Mihailide

I stop to catch my breath on the crest of a hill in Predeluţ.

It's late autumn with a blue-diamond sky. Nevertheless,

there is fresh snow fallen on the rugged tops of the

mountains and on the hedges of dark fir trees at the foot of

the Bucegi mountains – looking as if they were mounted

lancers. The snow is glistening.

I feel the tall grass, dried by the season, under my feet. On

the twisted and black branches of the old apple trees, red

fruit swing in the scented wind. Around the roots of the

some apple trees – there are spots of royal purple perennial

irises. Although poisonous flowers, I can’t resist their calling

beauty and I lift a few threads.

Back on track, I turn my bicycle towards Bran, I descend by

the Castel, pass by Vama Medievală, and ride along Turcu

River to the place where it sweeps in Șimon stream. Then I

turn left and head towards the Brandeberg guesthouse. Here

I securely park my "Pegas". My destination is not the hotel

but the building across the street, Parascheva Holy Church,

on 340, Iancu Gonţea Street, whose frescoes were painted

about three centuries ago by Nicolae Zugravu from Turcheş

– Săcele. It is believed that he also put his talent at work at

the Three Holy Hierarchs Monastery in Iași.

My objective as a traveller is not the church but the "cultural

and medico-historical heritage" provided by the resting

places around this holy edifice. Many important Romanian

intellectuals – several of them physicians – were born in the

village of Bran, today a tourist attraction, but also in the

nearby villages; many sleep their eternal sleep in the

cemetery of Şimon village, under crosses with their names

engraved on them. I intend to leave the bunch of irises on

Iancu Gonţea’s grave… The surrounding mountains and the

forests that reached the yard of my house when I was a child

were like the lords of the land for me... It is at Şimon that I

built a vault in order to make sure that I would not sleep my

eternal sleep anywhere else. "Today, a commemorative

plaque and the name of a street in Bran remind us of this son

of the region”, noted Emil Stoian, the brave chronicler of this

beautiful mountain village, to whom the inhabitants owe a

major contribution for preserving the image of those who

really meant something for the Romanian people. Such

people are numerous, in Bran: historians, philologists,

lawyers, physicians, actors, officers, priests, professors and

academicians; participants in the Great Union of 1918;

heroes of the two World Wars. I have met some of the

physicians…

78

Found at the location, I feel disappointed: where is the

tomb? I am told to go two kilometers uphill on the right side

of the road. This time I decide to walk. Indeed, after passing

the Primary School, on the yellowish wall of which a thin

marble plaque reminds that the scholar attended his first

classes "here", I pass by the house and the yard where he

was born and spent his childhood, its gate always locked, and

arrive at the church dedicated to St. Nicholas, standing a few

meters retreated from the main street. Here, behind the

building is a small cemetery. At its end, close to the hill, I

finally find the vault: "Fam. Prof. Dr. Doc. Iancu Gonţea" with

two rows of vertical crypts! It looks rather like a bunker. In

the crypt by the side of the teacher lies his wife, Dr. Lucia L.

Gonţea (1907-1998, born Popescu) buried 22 years after the

professor.

From an oval photograph, embedded in the austere concrete

wall, the professor gives me a harsh look. Where should I put

the irises brought as a modest homage? It's difficult to find

your way between the graves...

I have synthesized ergo-biographical data regarding Prof.

Iancu Gonţea in a book [2], using sources coming mainly

from the archives of the medical-historical documentation

library of the National Public Health Institute of Bucharest,

an institution whose enrichment with new information

(manuscripts, photos, video tapes, books, magazines, etc.)

and modern digitization was stopped for various reasons...

Iancu Gonţea was one of my professors in my fourth year at

the Bucharest Faculty of General Medicine. Decades have

gone by. Before proceeding to "serious things", I ask the

reader's permission to reproduce a few paragraphs, surely

forgotten by the reader, perhaps funny, from the notes

about the professor of the Food Hygiene Department, who

was born in Şimon and returned there at the end of his life.

"We were two groups of fourth-year students of General

Medicine, huddled in front of the laboratories of the

Institute of Hygiene in Bucharest, where we were to take an

oral exam in Food Hygiene. The professor – an unforgettable

person... tall, slim, with penetrating eyes and a Hemingway-

style beard, wearing an impeccable white gown – was sitting

at the teacher’s desk, on a podium, with the assistant group

on his right, and us, the wretched students (oh, how we cried

out for mercy knowing his exigency!), one step down, in

front of the examiners, at a tiled table full of Erlenmeyer

balloons, pipettes, tripods, test tubes and dropping bottles.

Usually, this type of final exam was the responsibility of the

associate professors. It was only exceptionally that the

professor would waste his time with us. Well, there we were,

living... the exception! Each of us picked from a jar the ticket

with the subjects written on it, thought of them for a few

minutes and answered the three questions, in the order in

which they were typed.

After ending our monologues (rather scanty, more often

than not), followed a dialogue with the professor, Iancu

Gonţea himself. At the end, he wrote down the grade that

each of us deserved in our grade-books and we tiptoed out

of the lab. In the hall, we were approached by our classmates

who, browsing through their notebooks, were trying to learn

everything they hadn’t learnt until then, before entering the

lab room „to have their heads cut off".

– What subject did you pick? Does he also ask questions from

«the practical experiments»? Is he harsh, is he kind? What

grade did you get? Many of the questions were difficult to

answer promptly... At a certain moment, one of the best


79

students of our class came out of the lab, almost bursting

into tears, obviously confused.

– What happened? What subject did you get?

– The third question, she explained us, as she started to feel

better, was about the trophic content of the main foods. I

explained how many proteins, lipids, fats and calories can be

found in cow's milk, eggs, fish, chicken and I don’t know what

else I mentioned... I couldn’t realize whether he was satisfied

or whether I had gotten it all wrong. I finished what I had to

say, but then he asked me additional questions, looking at

me over his glasses:

– «What about ordinary vegetables, which of them have a

higher vitamin content?» I gave the wrong answers, I

stammered and then I said: carrots, spinach, tomatoes...

Whatever!

– «What a-bout-par-sley?» he asked. I was as quiet as a fish.

Total silence. He gave me the right answer and explained

why his question was so important. Then he added:

– «Veronica, Veronica! You didn’t really like Food Hygiene…»

And then I saw him write 5 (five) in my grade-book and sign

it. «You should come in the autumn to get a higher grade! he

said, probably thinking that I would otherwise lose my

scholarship…

The professor's question was not tricky, he had indeed told

us in his lectures that parsley contains more vitamin C than

lemon, orange or cabbage and, in addition to that, it also

contains vitamins A, B1, B2, B6, K and E, as well as all the

minerals useful to the body. Parsley is an antioxidant,

antiallergic, antitumoral, which stimulates the gallbladder

secretion, maintains elasticity of the vessels, and I can no

longer remember now, more than half a century later, what

other wonders we owe to this herb, commonly used for

flavoring and adorning dishes!

Veronica had only remembered what the professor’s

assistant had told us at a seminar, smiling, about the

qualities of this ancient vegetable: «It also ensures the good

functioning of the genitals and even has a powerful

aphrodisiac effect! »”[3]

Writing about himself in a curriculum vitae requested by the

Academy of Medical Sciences (AMS), whose member he

became, professor Iancu Gonţea believed that he had set a

"new trend in the science he practiced, which was seen not

only as food hygiene, studied separately from the man (in a

narrow technical-sanitary concept), but as the science of

biomedical, psycho-social, and economic relations between

man and food"[4]. He has the merit of having contributed to

determining the nutritional requirements in relation to one's

occupational and environmental conditions, «for the first

time demonstrating that physical activity increases protein

and calcium needs, as well as vitamin C consumption, [and

that] exposure to chemical noxae heightens the metabolism

of thioamide acids and of ascorbic acid, increasing the needs

of the body.»

In the same CV requested by the Academy of Medical

Sciences, the professor listed the procedures he had devised

for the biochemical control of vitamin nutrition status, as

well as the methodology for studying the biological value of

food, both highly appreciated by international scientific

bodies.

The professor was to be awarded an important international

prize (Maurel) as well as the silver medal in food science for

his contribution regarding natural anti-nutritional

substances in food and animal feed. I. Gonţea also

demonstrated that no food is complete and set up an

original classification of foods (by groups), embraced by

experts of his time, in keeping with the benefits and the

deficiencies of various food categories."[5]

Given their originality and practical value, based on rigorous

laboratory and field research, many of his writings have been

translated into widely-circulated foreign languages. They

cover the fields of effort physiology, pathophysiology, and

medical clinic, but most of them include research on human

nutritional needs under different physiological, occupational

and environmental conditions: "Food Control" (1956), "Food

Ration" (1956), "Rational Nutrition of Women during

Maternity and Its Importance for Mother and Child Health"

(1958) can be considered as major landmarks in medical

literature, at least in the Romanian one. The last of the books

mentioned were updated by the author, translated into

German, and published by the prestigious publishing house

80

Gustav Fischer of Jena in 1965. Having received excellent

reviews, this monograph was requested, from the German

publishing house, by Dai-lichi Co. Ltd. Publishing House in

Tokyo and became the first book by a Romanian scientist

published in Japan, in 1974.

In 1963, the Medical Publishing House (Bucharest) released

"The Bases of Nutrition". Three years later, another book

was published: "Natural Anti-Nutritional Substances in Food

and Animal Feed" (in association with Paraschiva Şuţescu,

Ph.D.), subsequently translated into French and published by

Vigot Frères Publishing House, in association with prof.

Raymond Ferrando PhD (Paris, 1967), as well as into English,

and published by Karger Publishers in Basel (Switzerland) [6]

as well as in New York (1968). The Academy of the Socialist

Republic of Romania awarded professor Gonţea the "Victor

Babeş” prize for this book. Among the books that were

published, almost every year, two titles still stand out,

several decades later:" A Genetic Leap in the Nutritional

Value of Corn – the Past and Present of this Cereal” (Ceres

Publishing House) and "Alcoholism" (Medical Publishing

House, 1976), an insight from the point of view of preventive

medicine into the use and over consumption of alcoholic

drinks – "considered to be a serious problem on a national

level".

Professor Iancu Gonţea won high recognition in the scientific

events he was invited to — international congresses and

symposiums (Dresden, Moscow, where he accompanied the

Romanian delegation as an expert in nutritional issues at

C.A.E.R. meeting, 1969), at New Castle ("Women’s Nutrition

during the Reproductive Cycle", 1971), Mexico (where he

presented a paper titled "Nutrition and Anti-Infectious

Defense in Humans" ), Austria ("The Effects of Sugar Abuse")

etc. He received national and international awards and

diplomas.

Under a Decree of the State Council of the Socialist Republic

of Romania (153/1971), the professor was awarded the

"Sanitary Merit”, alongside other scientists rewarded "for

the contribution to the Party's policy in the field of public

health in our country". The chairman of the Council at the

time was N. Ceauşescu, while the minister of health – Prof.

Dr. Dan Enăchescu.

The fact that the romanian scholar did not also become a

member of the Academy is rather amazing, since, forgive my

insolence, many others were comfortably sitting in the

"immortals"' seats of the Academy of the Socialist Republic

for (scientific!) achievements, which, compared to his own,

were a lot less significant...

*

Who would have thought that professor Iancu I. Gonţea – a

former military physician (promoted major in 1948), hence

a person whose past and family had been under the close

scrutiny of the army's newly set-up personnel department

and who had a "healthy" origin (being the son of a shepherd,

born in the village of Şimon, on February 10, 1907), and

therefore, seeming to be imbued with socialist "principles"

and "ethics" – was to be placed under surveillance by the

Securitate (being the subject of two files, "I. 498910")? [7]

He maintained correspondence with scientists from all over

the world; often travelled to Western countries but also to

the Soviet Union; he attended medical conferences; worked

in the field of food hygiene, this having a great social impact.

He represented the Socialist Republic of Romania in the

World Health Organization. All this supposed that his loyalty

to the "party and to the socialist homeland" were to be

continuously tested by the "state bodies"...

The "vigilance" of the Securitate also translated into an

internal decision issued on November 18, 1969, regarding

the preservation of his "informative" file in the Operational

Fund, under no. I. 715753, coming from the 3rd Directorate

of the feared institution…

What was pursued Iancu Ion Gonţea accused of?

That "he was a member of the Iron Guard, working in the

Sanitary Department of its Documentary Studies Center."

That, "he was a major in the bourgeois army" (a member of

the contingent of officers who took the military oath before

the King). Later on that "he maintained correspondence with

people from abroad, such as Prof. R. Ferrando (France) and

foreign publishing houses." In an informative ("strictly

secret") note obtained by major I. Ion, at agent "Gabriel"

home and dated April 17, 1967, he declared that he met the

person under surveillance during his studies at the Andrei

Şaguna High School (1924-1927) and added that Iancu

Gonţea (I.G.) "was a very good student, who graduated at

the top of his class".


81

The note provided biographical data, generally consistent

with that provided by Gonţea in his résumés. I.G. seems to

been the son of poor peasants from Bran; he was not

perform any legionary activities, although his uncle, a history

teacher, dr. [Ioan] Moşoiu, "who was also the manager of

the high school (the Andrei Șaguna Romanian Orthodox high

school in Braşov) was known for his involvement in the

legionary activity (he was the Commander of one of its local

branches). After graduating from high school, I.G. joined the

Medico-Military Institute (Bucharest) and "Gabriel" went to

Prague. After 1948, they met again in Bucharest, on a daily

basis, since I.G. taught at the Institute of Hygiene.

Despite being rather ill (suffering from diabetes), I.G. was

very active, becoming a professor and the head of the Food

Hygiene Department (Bucharest Institute of Hygiene). He

was highly valued as a specialist, "Gabriel" convincingly using

the communist jargon of the time: he "combines theory with

practice and links laboratory research with practical

activities, such as supervising in bakeries, canteens, etc." He

had a vast journalistic activity, "Gabriel" citing in I.G.'s

defense his contributions to Scânteia and Economic Life

newspapers, ahead of the papers published in specialized

magazines…

Next came a significant detail: although generally he did not

have an active social life, I.G. celebrated his 60th birthday by

organizing a "comradely lunch at the Faculty of Military

Medicine". Among the guests featured professor [Nicolae]

Nestorescu, a microbiologist and immunologist (who also

was a former military physician) and lecturer Coman

Petrescu, PhD (a pediatrician dealing with rational child

nutrition). In "Gabriel"’s opinion, allegations that I.G. had

been involved in the legionary movement activities as a

student were simply "unfounded rumors."

However, in his Note, major I. Ion seemed keen to show his

superiors how cautious he was: "Since I.G. is known by the

Third Department (of the Securitate) as a former member of

the Iron Guard, the agent will have to inform us of any data

backing this assumption. In addition to that, the

correspondence with foreigners will be kept under

observation." Next came a list of names – French and

German researchers and professors from (Paris) and

(Heidelberg).

Here is what agent "Titi", who "kept him under observation

during his teaching activities”, wrote: "Always punctual,

having a commanding attitude, he teaches the students

notions of food hygiene during his two-hour lecture. During

his lectures he seems to speak with passion, having a

dignified attitude. From talking to other students, the source

found out that professor Gonţea is very demanding during

exams, asking the students to reproduce all the details, or

better said the whole lecture, word by word. He does not

hesitate to turn students out over the slightest mistake. His

behavior gives the impression of a modest man, deeply

involved in his profession."

Elly – a professional informer

In Iancu Ion Gonţea's file, there is a note received by

captainV. Ovidiu, on April 19, 1957, from agent "Elly",

reeking of antipathy towards I.G., a text in which one can

hardly tell the truth from "pure" lies. It is difficult, if not

downright impossible, to check these allegations because

the informer, hiding under the pseudonym given her by the

Securitate, seems to be a professional of delation, citing

people (giving their full names and the position held in the

Institute) who could allegedly back her allegations, but who

today, 60 years later, are most certainly dead...

"I inform you", wrote Elly, "that Dr. I.G., associate professor

of nutrition at the Faculty of Medicine, living at 244,

Dorobanti Street, phone 7.66.29, claims to be

«untouchable» because he is backed by Acad. Ștefan Milcu

and Acad. N. Lupu, who are «indebted» to him.

I.G. is the author of numerous fake public documents and

characterizations (within the IMF – Institute of Medicine and

Pharmacy), helped by former head of the personnel

department At.). All these facts are known by the

management. Dr. I. Per. from the Hygiene Institute,

Laboratory of Food Chemistry, 1, Leonte Street, can provide

82

references in this respect."

After this "introduction," "Elly" wrote that she knew I.G.

since November 1954. "I know that he was a legionary,

working in the cabinet of another Iron Guard physician, Dr.

Ru, within the Legionary Ethics Committee – at the time, the

steering committee of the Faculty of Medicine (?). At that

time he worked wearing a green, Iron Guard shirt; at Iron

Guard rallies he carried banners reading Nu merus nullus

(sic!) and Nu merus claus (sic!). prof.dr. I.I.N., manager of the

Institute of Physiology of the R.P.R. Academy, phone 4.20.59

(home) and Dr. Eug. D.), phone 7.31.16 (home) can give

references about his activity at the time. Among the acts of

hooliganism, I can mention the ones I heard about from Dr.

Eug. D., namely that Assoc. Prof. Dr. I.G., under the legionary

régime, tried to devastate the Cantacuzino Institute, kicking

the doors when he entered the rooms, destroying laboratory

equipment, etc. In the Military Sanitary Institute where he

worked for some time, the whole institute knew him as a

"passionate Iron Guard member" (Dr. Iac., Assistant at the

physiology department, tel. 3.27. 90 ,home, can give

references about this). In the bourgeois army, he was highly

regarded because of the wealth he still holds, to a great

extent:

- Mansion in Călimanesti

- Estate and mansion in Bran

- Houses in Bucharest

- Car etc.

Later on, Assoc. Prof. I.G. proved to be a hostile element,

pleading in favor of Antonescu's criminal actions against the

USSR. References: Dr. Eug. D. and Dr. P.

Thus, Assoc. Prof. Gonţea maintained ties with his former

collaborators from the Legionary Nest, Assoc. Prof. Pr. Gh.,

from the Physiology Department, with Tudor G., also from

the Physiology Department, with G. Maria from the same

department, about whom I will tell you in detail further

down. Assoc. Prof. I.G. has remained the same reactionary

person, nurturing sympathy for the Iron Guard, and still

indulging in hooliganism. Here are some facts:

1) He encourages the personnel not to apply for higher

positions since exams are "based on the Russian model and

have a temporary character". References can be given by C.

Adrian, assistant at the Physics Faculty, phone 2. 68.09

2) Assoc .prof. I.G. sent two articles for publication to the

Institute of Physiology of the Academy of the R.P.R. (People's

Republic of Romania), registered with no. 36 / 6.III.1957 of

the Nutrition Department:

- The bibliography of the first article includes 13 works, none

of them Soviet.

- The bibliography of the second article includes ten works,

all of them English and American.

- This amounts to hostile behavior towards Soviet science,

and within the department, which contrary to the ideological

orientation of the scientific research in the R.P.R.

3) He considers himself a "great patriot and a great

Romanian". Under this mask, Assoc. Prof. I.G. hides his

ferocious anti-semitism and hatred against elements

dedicated to the working class. References: 1. Gabriela from

Caritas, phone 2.90.40 who was an assistant at the

Department of Nutrition, Dr. D. Eugen, phone 7.31.16; M.

Maria. St. Constintin Street, No… Petre P. from the Cotroceni

Hygiene Institute.

4) Assoc. Prof. Gonţea Iancu (hereafter names were blacked

out by the CNSAS) – nurse G. Maria swore to me, in the

autumn of 1955, on the health of her child, that, as head of

the Nutrition Department, he had given her extra paid hours,

the equivalent of a part-time job, [but] from the date of

January 1, 1955 to September 1, 1955, he obliged her to give

him 1/2 of her part-time wage. G. Maria told me this out of

despair because (redacted by the CNSAS) his fabulous wealth

helped him back the interests of the Iron Guard. [And] after

she gave him this money, "which he literally grabbed from

her and which were part of her due", as a reward, assoc.prof.

Gonţea gave her the sack. The reason was another

subordinate, dr. Şuţescu Paraschiva (anonymized words by

the CNSAS) who [becoming a favorite] continued to work

with I.G. G.Maria told me all this on the way between

Ardealul Avenue and Plevnei Street, as she was going

towards Progresului to the Rectorate of the Institute of

Medicine and Pharmacy.

5) At the Nutrition Department, Assoc. Prof. Gonţea sells

overpriced wool and veal meat from his estate in Bran to the

staff, whom he obliges to buy, threatening to treat them

badly if they don't. Assist. A. C. can give references, phone

3.11.10.

6) (Anonymised paragraph by the CNSAS) G. Maria was a

notorious Iron Guard member, the daughter of the richest

merchant in Constanța who lived in the countryside in

Bulgaria until 1956, when she brought him back to Bucharest

for good since "rich people are no longer oppressed as they

used to be", according to her own words. G. Maria worked

with the Legionnaires, being... (redacted). Thus she helped

them set up camps in the V. Roaită resort and her father

helped by providing food and transportation.

7) As far as his behavior towards students is concerned, I can

mention that several of them have lodged complaints about

his demagogic manifestations with the Dean’s Office of the


83

Faculty of Medicine, but to no avail. References can be given

by student P. Aurel from the sixth year. His attitude towards

the young employees of the Institute of Medicine and

Pharmacy has remained fierily reactionary and he is doing

his best to exclude those who had worked in ministries

representing our régime. I am attaching the original

statements by Prof. N., whom Assoc. Prof. Gonţea Iancu told

that he would do his best so that Dr. Maria Mih. and her

husband, C. Adrian, who had worked at the MAI [Ministry of

Internal Affairs ] would be sacked. C. Adrian was summoned

to the C.C. of the P.M.R. for a mission, which Gonţea branded

as a dangerous element for the reactionary clique he is a

member of. (I should mention that the summons took place

a few months after the appointment of assistant C. within

the Medicine Faculty).

8) About Assoc. Prof. Gonţea Iancu's son, whose name is

Gonţea Liviu, a fourth-year student at the Faculty of

Medicine, I know that he was under investigation by the

Ministry of Internal Affairs over hooliganism when he was a

high-school student. I mention that Gonţea Iancu was

connected to Lupaş Tudor, who provided him with articles

translated from Hungarian, which had been broadcasted on

the radio, which Gonţea Liviu handed to the students in his

group. In a conversation with Tudor Geor., Lupas's uncle,

who worked in the physiology laboratory, told me that «the

guilty people are free while his nephew is in prison.»

When I asked him if Gonţea’s son had been involved, he did

not give a straight answer, but made me understand that he

had."

(signed) Elly

We find ourselves in 1957, a few months after the Hungarian

revolution (called "counter-revolution" by the Communists),

when the vigilance and coercive measures of the Securitate

got a new "boost", stimulating the activity of informants.

Moreover, on October 27, 1956, in university cities, students

were out in the streets demanding an improvement in living

conditions, the removal of the Russian language from the

educational curricula, and the liberalization of social life,

demands which were followed by reprisals and arrests.

Students and professors thus becoming a target of the newly

established Ministry of State Security, an institution distinct

from the Ministry of Internal Affairs, at the time led by

Alexandru Draghici.

A year later, in June, a plenary session of the C.C. took place,

announcing a return to the struggle against bourgeois

ideology, criticism of intellectuals accused of snobbery,

cosmopolitanism, apoliticism, negativity etc. Thus, the

departure of the Soviet troops who had been stationed on

Romanian territory for 14 years, did not seem to be

auspicious to acts of dissent, especially from those who had

had certain political views in the past, even if they had let

themselves be carried away; on the contrary, it meant

increased vigilance8.

Ellyˊs denunciations were obviously not based on

"proletarian intransigence" or "ethical" reasons, but rather

on personal, vindictive motives, which, after so many years,

cannot be properly weighed. It is possible, however, that the

"witnesses" mentioned by the informer may have

considered themselves, for various reasons, harmed by the

teacher (possibly by the exigencies that he imposed) or

"stopped" in their desire for rapid ascension in the

professional field or on the social ladder. In that period, the

"weapon" at hand chosen by an informant in ensuring his

success was invoking an alleged Iron Guard activity, or at

least sympathy, on the part of the "target".

One of the graduates of the Faculty of Cluj (whose name was

blacked out), was "promoted", as early as his student years,

to a party activist, to the "Central Committee structure”!

Starting in 1949, he held important positions in the state

hierarchy: adviser to the minister of Health, then Sanitary

General Inspector. He became pro-rector of the Institute of

Medicine and Pharmacy in Bucharest (IMF) then, based on

this rapid ascension and, of course, "being a valuable

person", was named associate professor. (This rapid fast-

lane promotion took barely six years).Since 1955 he engaged

in research as head of department at the Hygiene and Public

Health Institute in Bucharest. How could "Elly” not cite his

name and indicate him as a credible witness in order to

assess professor Gonţea's activity and behavior?

And what about another rival, born in 1884? The latter

hoped that, thanks to the protection of his administrative

superiors and by "revealing" I.G.'s alleged "Legionnary

activity" and backing Elly's allegations, he could indefinitely

extend his teaching term, in no matter what department, if

Gonţea could be forced to give up the position he held

«based on merit».

Nevertheless, we should mention that Ellyˊs detailed

statements found in this file were not backed by any "notes"

or testimonies given by the witnesses she cited.

After August 23, 1944, the issue of the legionnaires had

become a major concern for the new power. In 1945, former

legionnaire’s members who were deemed as dangerous

were arrested and sent to labour camps. Others were to be

determined to become – and truly became – collaborators

of the Communist Party, following Ana Pauker's

intervention. On December 10, 1945, the Ministry of Internal

Affairs issued an order "legalizing" some of the former Iron

Guard members, who no longer posed a threat to the State

84

and who had offered their services to the new régime. It was

a bluff: the trio made up of Ana Pauker, Teohari Georgescu

(minister of Internal Affairs) and KGB general Nicolski were

later accused of having facilitated the infiltration of former

Iron Guard members into the Communist Party. As a

consequence, the three former Communist dignitaries were

ousted.

At that time, however, the Legionnary Movement ghost had

reappeared and informant "Elly" seized this opportunity to

accuse Iancu Gonţea. It is true that many intellectuals,

particularly younger ones, had sympathized with the

Legionnary Movement in the 1930s, even though they later

disavowed this affinity (see the notorious cases of Mircea

Eliade, Eugen Ionesco, Emil Cioran.) Many intellectuals from

the area of Braşov – Bran (eg, the great philologist Sextil

Puşcariu), shared rightist, or even Iron Guard sympathies, an

ideological confusion which they later regretted; among

them there were also many physicians who had acquired

some notoriety in their profession.

**

I once asked an older friend: why is there so much hatred

towards a man who, through his knowledge and hard work,

dedicated his life to medicine for the public welfare?

– "The he lazy man will throw stones only at the tree full of

fruit, so that he can collect the fallen fruit effortlessly", my

friend replied. "And then, we know from the Gospel that 'no

good tree will bear bad fruit, nor will a bad tree bear good

fruit.'"

References:

1. Stoian, Emil, „Portrete din Bran”, Dealul Medicilor Publishing

House, Braşov, 2002

2. Mihailide, Mihail, „Insolitul ospăț al unui devorator de arhive”,

Viaţa Medicală Românească Publishing House, 2017

3. Ibidem

4. Medicine History Documentary Library, National Institute for

Public Health, Bucharest, Iancu Gonţea File.

5. Ibidem

6. Ib. id. Reper 2

7. National Council for the Study of Security Structure Archives

(CNSAS), Central Archives Department, Operative file Gonţea Ion-

Iancu, cote 498910, vol.I and vol.II * The files were studied by 10

other people between April 5, 1969 and March 3, 1976).

8. Collective, coordinator Valentina Bilcea, „Istoria românilor.

Date Fapte. Oarneni”; Foreword: Professor Adrian Cioroianu Ph.D.,

Meronia Publishing House, Bucharest, 2018


85

ADMINISTRATIVE ISSUES

Guidelines for authors

Thank you for your interest in Romanian Journal of Military Medicine. Please read the complete Author Guidelines carefully prior to submission, including the section on copyright. To ensure fast peer review and publication, manuscripts that do not adhere to the following instructions will be returned to the corresponding author for technical revision before undergoing peer review. Note that submission implies that the content has not been published or submitted for publication elsewhere except as a brief abstract in the proceedings of a scientific meeting or symposium. Once you have prepared your submission in accordance with the Guidelines, manuscripts should be submitted online at [email protected]. We look forward to your submission.

EDITORIAL AND CONTENT CONSIDERATIONS Aims and Scope Romanian Journal of Military Medicine (RJMM) is the official journal of the Romanian Association of Military Physicians and Pharmacists. The Journal publishes peer-reviewed original papers, reviews, meta-analyses and systematic reviews, and editorials concerned with clinical practice and research in the fields of medicine. Papers cover the medical, surgical, radiological, pathological, biochemical, physiological, ethical and historical aspects of the subject areas. Clinical trials are afforded expedited publication if deemed suitable. RJMM also deals with the basic sciences and experimental work, particularly that with a clear relevance to disease mechanisms and new therapies. Case reports and letters to the Editor will not be considered for publication.

Editorial Review and Acceptance The acceptance criteria for all papers and reviews are based on the quality and originality of the research and its clinical and scientific significance to our readership. All manuscripts are peer reviewed under the direction of an Editor. The Editor reserves the right to refuse any material for review that does not conform to the submission guidelines detailed throughout this document, including ethical issues, completion of an Exclusive License Form and stipulations as to length.

ETHICAL CONSIDERATIONS Principles for Publication of Research Involving Human Subjects Manuscripts must contain a statement to the effect that all human studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the Declaration of Helsinki (as revised in Brazil 2013), available at http://www.wma.net/en/30publications/10policies/b3/index.html. It should also state clearly in the text that all persons gave their informed consent prior to their inclusion in the study. Details that

might disclose the identity of the subjects under the study should be omitted. Photographs need to be cropped sufficiently to prevent human subjects being recognized (or an eye bar should be used).

Registration of Clinical Trials We strongly recommend, as a condition of consideration for publication, registration in a public trials registry. Trials register at or before the onset of patient enrolment. This policy applies to any clinical trial. We define a clinical trial as any research project that prospectively assigns human subjects to intervention or comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Studies designed for other purposes, such as to study pharmacokinetics or major toxicity (e.g., phase 1 trials) are exempt. We do not advocate one particular registry, but registration with a registry that meets the following minimum criteria: (1) Accessible to the public at no charge; (2) Searchable by standard, electronic (Internet-based) methods; (3) Open to all prospective registrants free of charge or at minimal cost; (4) Validates registered information; (5) Identifies trials with a unique number; and (6) includes information on the investigator(s), research question or hypothesis, methodology, intervention and comparisons, eligibility criteria, primary and secondary outcomes measured, date of registration, anticipated or actual start date, anticipated or actual date of last follow-up, target number of subjects, status (anticipated, ongoing or closed) and funding source(s).

Plagiarism Detection The journal employs a plagiarism detection system. By submitting your manuscript to this journal you accept that your manuscript may be screened for plagiarism against previously published works. Committee on Publication Ethics The journal subscribes to the principles of the Committee on Publication Ethics (COPE).

MANUSCRIPT CATEGORIES AND SPECIFICATIONS All articles, with the exception of Editorials, must contain an abstract of no more than 250 words. Abstracts for original articles should be formatted into subheadings, as detailed below. Titles must not be longer than 120 characters (including spaces).

Editorials These are invited by the Editor-in-Chief or their delegated editor, and should be a brief review of the subject concerned, with reference to and commentary about one or more articles published in the same issue of RJMM. Editorials are generally 1200–1500 words, may contain one table or figure and cite up to 15 references, including the source article [this should be cited as Military Med. Today (year); (vol): [this issue].

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Review Articles RJMM welcomes reviews of important topics across the scientific basis of medicine, and advances in clinical practice. Most published reviews are in response to editorial invitation, including thematically related “mini-series” of reviews. Authors considering submitting a review for RJMM are advised to canvas their possible review with the Editor-in-Chief or a colleague editor; this avoids early rejection if the subject matter is not deemed a high priority for the Journal at the time of submission. Reviews are limited to 3500–5000 words, with an abstract of up to 250 words and up to 75 references and 3–7 figures or tables.

Meta-Analyses or Systematic Reviews RJMM particularly welcomes submission of Meta-Analyses and Systematic Reviews, which underpin evidence-based medicine. Guidelines for preparation of Meta-Analysis and Systematic Reviews are similar to other reviews, and articles are subject to the usual peer review process. Meta-Analyses and Systematic Reviews have a word limit of 3500–5000 words, with an abstract of up to 250 words and up to 75 references and 3–7 figures or tables.

Original Articles (including clinical trials) RJMM welcomes original articles concerned with clinical practice and research in the fields of medicine. Papers can cover the medical, surgical, radiological, pathological, biochemical, physiological, ethical and/or historical aspects of the subject areas. Clinical trials are afforded expedited publication if deemed suitable. RJMM also deals with the basic sciences and experimental work, particularly that with a clear relevance to disease mechanisms and new therapies. Original articles are limited to 3000 words, with an abstract of up to 250 words and up to 50 references and 3–7 figures and tables.

Education and Imaging The Editors welcome contributions to the Education and Imaging section. The purpose is to present imaging for the evaluation of unusual features of common conditions or diagnosis of unusual cases. Contributions will be reviewed by the Education and Imaging Coordinating Editors. The format of the Images pages involves two parts, each of which will occupy up to one journal page. In part 1, a case will be described briefly, including a summary of the presentation, clinical features and key laboratory results. One to two key images will then be presented. It is helpful to the reader if the author responds to questions that follow from the images of the case, such as ‘What is your diagnosis? What are the features indicated on the CT scan? What is the differential diagnosis?’ Part 2 will briefly describe the imaging features, particularly those that lead to diagnosis or which are critical for management. Differential diagnosis should be mentioned. It will be useful to include either further images or pathological details that validate the imaging diagnosis. Occasionally, presentation of analogous cases or related images from a similar case might be appropriate. Please include between one and three references to definitive studies and appropriate reviews of the subject. The format of the Images page involves a brief background to and description of the disorder of interest together with two figures of high quality. Colored photographs are encouraged. The submission may take the form of a case report or may illustrate particular features from more than one patient.

MANUSCRIPT PREPARATION Style Manuscripts should follow the style of the Vancouver agreement detailed in the International Committee of Medical Journal Editors’ revised ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication’, as presented at http://www.ICMJE.org/. Spelling. The journal uses US spelling and authors should therefore follow the latest edition of the Merriam-Webster’s Collegiate

Dictionary. Units. All measurements must be given in SI units as outlined in the latest edition of Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Royal Society of Medicine Press, London). Abbreviations should be used sparingly and only where they ease the reader’s task by reducing repetition of long technical terms. Initially use the word in full, followed by the abbreviation in parentheses. Thereafter use the abbreviation. Trade names should not be used. Drugs should be referred to by their generic names, rather than brand names.

Parts of the Manuscript The manuscript should be submitted in separate files: title page; main text file; figures. Title page The title page should contain (i) a short informative title that contains the major key words. The title should not contain abbreviations; (ii) the full names of the authors (if possible, not more than 5 authors per title); (iii) the author's institutional affiliations at which the work was carried out; (iv) the full postal and email address, plus telephone number, of the author to whom correspondence about the manuscript should be sent; (v) disclosure statement; and (vi) acknowledgements. The present address of any author, if different from that where the work was carried out, should be supplied in a footnote. Disclosure statement The source of financial grants and other funding should be acknowledged, including a frank declaration of the authors’ industrial links and affiliations. In the case of clinical trials or any article describing use of a commercial device, therapeutic substance or food must state whether there are any potential conflicts of interest for each of the authors: failure to make such a statement may jeopardize the article being sent out for peer-review. Acknowledgments The contribution of colleagues or institutions should also be acknowledged. Thanks to anonymous reviewers are not allowed. Main text As papers are double-blind peer reviewed the main text file should not include any information that might identify the authors. The main text of the manuscript should be presented in the following order: (i) abstract and key words, (ii) text, (iii) references, (iv) tables (each table complete with title and footnotes), (vii) figure legends. Figures and supporting information should be submitted as separate files. Footnotes to the text are not allowed and any such material should be incorporated into the text as parenthetical matter. Abstract and keywords Original articles must have a structured abstract that states in 250 words or less the purpose, basic procedures, main findings and principal conclusions of the study. Divide the abstract with the headings: Background and Aim, Methods, Results, Conclusions. The abstracts of reviews need not be structured. The abstract should not contain abbreviations or references. Three to five keywords should be supplied below the abstract and should be taken from those recommended by the US National Library of Medicine’s Medical Subject Headings (MeSH) browser—(http://www.nlm.nih.gov/ mesh/meshhome.html). Text Authors should use subheadings to divide the sections of their ma-nuscript: Introduction, Methods, Results, Discussion Acknowledg-ments and References. References The Vancouver system of referencing should be used. In the text, references should be cited using superscript Arabic numerals in the order in which they appear. If cited only in tables or figure legends, number them according to the first identification of the table or


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figure in the text. In the reference list, the references should be numbered and listed in order of appearance in the text. Cite the names of all authors when there are six or less; when seven or more list the first three followed by et al. Names of journals should be abbreviated in the style used in MEDLINE. Reference to unpublished data and personal communications should appear in the text only. References should be listed in the following form: Number references in the order cited as Arabic numerals in parentheses on the line. Only literature that is published or in press (with the name of the publication known) may be numbered and listed; abstracts and letters to the editor may be cited, but they must be less than 3 years old and identified as such. Refer to only in the text, in parentheses, other material (manuscripts submitted, unpublished data, personal communications, and the like) as in the following example: (Chercheur X, unpublished data). If the owner of the unpublished data or personal communication is not an author of the manuscript under review, a signed statement is required verifying the accuracy of the attributed information and agreement to its publication. Use Index Medicus as the style guide for references and other journal abbreviations. List all authors up to six, using six and "et al." when the number is greater than six. Tables Tables should be self-contained and complement, but not duplicate, information contained in the text. Number tables consecutively in the text in Arabic numerals. Type tables on a separate page with the legend above. Legends should be concise but comprehensive – the table, legend and footnotes must be understandable without reference to the text. Vertical lines should not be used to separate columns. Column headings should be brief, with units of measurement in parentheses; all abbreviations must be defined in footnotes. Footnote symbols: †, ‡, §, ¶ should be used (in that order) and *, **, *** should be reserved for P-values. Statistical measures such as SD or SEM should be identified in the headings. Figure legends Type figure legends on a separate page. Legends should be concise but comprehensive – the figure and its legend must be understandable without reference to the text. Include definitions of any symbols used and define/explain all abbreviations and units of measurement Indicate the stains used in histopathology. Identify statistical measures of variation, such as standard deviation and standard error of the mean. Figures All illustrations (line drawings and photographs) are classified as figures. Figures should be numbered using Arabic numerals, and cited in consecutive order in the text. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. Preparation of Electronic Figures for Publication: Although low quality images are adequate for review purposes, publication requires high quality images to prevent the final product being blurred or fuzzy.

SUBMISSION REQUIREMENTS Manuscripts should be submitted online at [email protected] A cover letter containing an authorship statement should be included. The cover letter should include a statement covering each of the following areas: 1. Confirmation that all authors have contributed to and agreed on the content of the manuscript, and the respective roles of each author. 2. Confirmation that the manuscript has not been published previously, in any language, in whole or in part, and is not currently under consideration elsewhere. 3. A statement outlining how ethical clearance has been obtained for the research, particularly in relation to studies involving human

subjects, and animal experimentation. The institutional ethics committees approving this research must comply with acceptable international standards (such as the Declaration of Helsinki) and this must be stated. 4. For research involving pharmacological agents, devices or medical technology, a clear Conflict of Interest statement in relation to any funding from or pecuniary interests in companies that could be perceived as a potential conflict of interest in the outcome of the research. 5. For clinical trials, that these have been registered in a publically accessible database. If the above items are not included in the cover letter, manuscripts cannot be sent for review. Please also note that the cover letter does not require a detailed or lengthy description of the content or structure of the manuscript itself. Two Word-files need to be included upon submission: A title page file and a main text file that includes all parts of the text in the sequence indicated in the section 'Parts of the manuscript', including tables and figure legends but excluding figures which should be supplied separately. The main text file should be prepared using Microsoft Word, doubled-spaced. The top, bottom and side margins should be 30 mm. All pages should be numbered consecutively in the top right-hand corner, beginning with the first page of the main text file. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. For submission, low-resolution figures saved as .jpg or .bmp files should be uploaded, for ease of transmission during the review process. Upon acceptance of the article, high-resolution figures (at least 300 d.p.i.) saved as .eps or .tif files will be required.

PUBLICATION PROCESS AFTER ACCEPTANCE Accepted papers will be passed to production team for publication. The author identified as the formal corresponding author for the paper will receive an email, being asked to complete an electronic license agreement on behalf of all authors on the paper.

Accepted Articles The accepted ‘in press’ manuscripts are published online very soon after acceptance, prior to copy-editing or typesetting. Accepted Articles are published online a few days after final acceptance, appear in PDF format only, are given a Digital Object Identifier (DOI), which allows them to be cited and tracked. After print publication, the DOI remains valid and can continue to be used to cite and access the article. Given that copyright licensing is a condition of publication, a completed copyright form is required before a manuscript can be processed as an Accepted Article.

Proofs Once the paper has been typeset, the corresponding author will receive an e-mail alert containing instructions on how to provide proof corrections to the article. It is therefore essential that a working e-mail address is provided for the corresponding author. Proofs should be corrected carefully; the responsibility for detecting errors lies with the author. The proof should be checked, and approval to publish the article should be emailed to the Publisher by the date indicated; otherwise, it may be signed off on by the Editor or held over to the next issue.

Offprint A PDF reprint of the article will be supplied free of charge to the corresponding author. Additional printed offprint may be ordered for a fee.

COPYRIGHT, LICENSING AND ONLINE OPEN Details are on the Copyright Agreement Form that must be completed and signed when the Article is accepted.

Romanian Journal of Military Medicine

New Series, Vol. CXXII, No 2/2019, August

ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126

vol. cxxii no. 2/2019 august military medicine · cristian v. toma, cristian s. sima, daniel g....

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