Romanian Journal of Vol

Founded 1897 • New Series Romanian Journal of Vol. CXXII • No. 2/2019 • August Military Medicine

REVISTA DE MEDICINĂ MILITARĂ

• 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

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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) Mihai Moldovan (Denmark) C. Ionescu Târgovişte (Romania) Silviu Brill (Israel) Ioan Opriș (USA) Radu Ţuţuian (Switzerland) Cris S. Constantinescu (UK) Gerard Roul (France) Shyam Varadarajulu (USA) Daniel Dănilă (USA) Erwin Santo (Israel) Peter Vilmann (Denmark) Stergios Ganatsios (Greece) Adrian Săftoiu (Denmark) Victor Voicu (Romania) Ioanel Sinescu (Romania)

Scientific Publishing Committee Adrian Barbilian (Bucharest) Raluca S. Costache (Bucharest) Ovidiu Nicodin (Bucharest) Anda Băicuş (Bucharest) Dragoș Cuzino (Bucharest) Tudor Nicolaie (Bucharest) Cristian Băicuş (Bucharest) Camelia Diaconu (Bucharest) Ana Maria Oproiu (Bucharest) Andra R. Bălănescu (Bucharest) Mircea Diculescu (Bucharest) Carmen Orban (Bucharest) Mircea Beuran (Bucharest) Lidia Dobrescu (Bucharest) Bogdan A. Popescu (Bucharest) Ovidiu Bratu (Bucharest) Cosmin Dobrin (Bucharest) Dragoș Popescu (Bucharest) Daciana Brănișteanu (Iași) Dumitru Constantin Dulcan (Bucharest) Aurelian E. Ranetti (Bucharest) Dragoș Bumbăcea (Bucharest) Silviu Dumitrescu (Bucharest) Mugurel Rusu (Bucharest) Marian Burcea (Bucharest) Carmen G. Fierbințeanu (Bucharest) Carmen A. Sîrbu (Bucharest) Sofia Colesca (Bucharest) Cristian Gheorghe (Bucharest) Silviu Stanciu (Bucharest) Gabriel Constantinescu (Bucharest) Liana S. Gheorghe (Bucharest) Ion Țintoiu (Bucharest) Silviu Constantinoiu (Bucharest) Viorel Jinga (Bucharest) Daniel Vasile (Bucharest) Dan Corneci (Bucharest) Carmen Moldovan (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.

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Romanian Journal of Military Medicine, New Series, vol. CXXII, No 2/2019, August ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126

RJMM Founded 1897 • New Series Romanian Journal of Military Medicine 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

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

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

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

EDITORIAL

Academician General Victor Voicu at the anniversary

An anniversary is rather meant to reflect on the past, present too much to say... and yet! and future, being at the same time, and a reason for He chooses pharmacology and clinical pharmacology and the celebration. 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- On Wednesday, June 26, 2019, the book of Academician President of this High Authority from April 2018. 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

The life, work, efforts and achievements of a MAN cannot be our common ancestor - General physician and pharmacist reduced only to the previous sentence. Those who want to Academician p.m. (2003) Carol Davila is not only an learn more about the frankness and the visionary spirit of "energetic" man, but also an "energetic" spirit for those Academician Victor Voicu, can do that by making use of around him, for all of us, when through his vision, calm and "search engines", as they say nowadays. analytical spirit, he manages to clarify things and "indicate" the right direction to follow. Academician Nicolae Breban enlightened the thoughts of the audience when he pronounced the word "energetic", adding The release of the book, "Under the Sign of Hippocrates," it to the joy felt by those present at the release of the book I was for all participants, as well as for future readers, a previously mentioned. celebration of the spirit.

General Academician Victor Voicu, a descendent in time of

The editorial staff of the Romanian Journal of Military Medicine Wishes Happy Birthday! To Academician Victor Voicu

Honorary Editor

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

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- anxiety-related procoagulant action [3], while yet another ANTICOAGULANTS INTERACTIONS AND SSRIs-INDUCED studies reveal the lack of significant effect of sertraline over COAGULATION DYSFUNCTIONS coagulation in patients after an acute myocardial infarction [4]. Data in the literature regarding selective serotonin reuptake inhibitors (SSRI) treatment in patients diagnosed with An independent analysis of clinical trials published in the depressive disorders and cardiovascular pathology for which main electronic databases (PubMed, Cochrane, Medscape, they receive anticoagulants contain contradictions regarding and EMBASE), using keywords “anti-depressant”, “serotonin the magnitude of antidepressants’ effect over coagulation selective reuptake inhibitors”, “major depressive disorder parameters. (MDD)”, “coagulation”, “anticoagulants”, “paroxetine”, ”sertraline”, “escitalopram”, “citalopram”, “fluoxetine”, “fluvo- Currently available informations suggest the existence of a xamine”, “warfarine”, and “acenocoumarol” was performed. decrease in platelets serotonin due to serotoninergic Only articles published between 1996 and 2018 have been antidepressants action, and this phenomenon appears to be selected. explained by a pharmacogenetic mechanism, through serotonin transporter promotor gene (5-HTTLPR) poly- Specific inclusion and exclusion criteria had been formulated morphism [1, 2]. Also, it has been observed that serotonin- according to Table 1. nergic antidepressants could mitigate the depression- and

Corresponding author: Octavian Vasiliu MD 1 Dr. Carol Davila University Central Emergency Military Hospital, [email protected] Bucharest, Romania

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- Children and adolescents. blished. Heterogenous populations, where statis- Diagnoses of MDD, dysthymia, adjustment disorder with tical procedures didn’t allow a separate depressive features, bipolar depression, mixed depressive conclusion for patients aged over 18. and anxious disorder. Other disorders than those with a signi- Diagnoses according to DSM, ICD criteria, or compatible ficant depressive component with these classifications. Lack of substance related comorbidities. Intervention Any agent from the SSRI class. Other, non-SSRIs-antidepressants. Monitored anticoagulant treatment. SSRIs in combination with other antidepressants. Concomitant use of CYP450 iso-enzymes inductors or inhibitors. Supra-therapeutic doses of SSRI agents. Environment In-patient or out-patient. Unspecified environment. In vitro or in vivo analysis of coagulation variables. Primary and secondary Any coagulation-related indicator, like platelet count, Any trial without coagulation related variables bleeding time, prothrombin time etc. parameters as primary variables was Discontinuation of treatment due to severe adverse events excluded from the hematological domain, like gastro-intestinal bleeding, hemorrhagic stroke etc. Design Randomized clinical trials, open-label, single-blind or Unspecified design. double-blind, placebo-controlled or not, prospective or Lack of a specific method for coagulation retrospective trials, case control studies, case reports or monitoring case series. Language English, French, German, Romanian Other language except for those mentioned

A number of 9 trials corresponded to these criteria and were although not above the normal values [5]. Another trial included in analysis. A synthetic overview of the selected showed no significant influence of fluoxetine over mean studies is presented in Table 2. prothrombine time during warfarin treatment [6].

Escitalopram had no effect on coagulation according to one Table 2. Synthetic indicators for selected trials trial [5]. Overall number Mean duration of Age at inclusion of subjects interaction Fluvoxamine could induced an over-anticoagulation status n=391 n=2 n=3 during acenocoumarol maintenance treatment, unlike other 43.4 7.5 weeks 68 years old SSRIs used as controls [7]. Fluvoxamine effect over SD=70.9 SD=6.3 SD=19.9 coagulation is supported also by two cases treated with Minimum=1 Minimum=3 Minimum=45 Maximum=225 Maximum=12 Maximum=80 warfarine [8, 9]. Sertraline is relatively safe in patients after acute MI, as it Due to the fact that not all of the papers published contain induced no changes in bleeding time [4]. Sertraline could complete data, synthetic indicators were calculated using interfere with warfarine at circulating binding proteins and only those studies which included specified variables, like displaced the anticoagulant, increasing its free fraction [10]. the number of participants, mean duration of treatment or In conclusion, escitalopram, sertraline and fluoxetine seem the patients’ age at inclusion. to be quite safe during anticoagulant treatment, while The most relevant research data are presented in Table 3. fluvoxamine has a tendency for inducing an over- anticoagulation status. Not enough data have been found to SSRIs as a pharmacologic class induced lower serotonin formulate a conclusion regarding paroxetine and citalopram, levels in the patients’ platelets [1] and had a significant effect but these agents seem safer than fluvoxamine, in trials who over several indicators of coagulation [3]. compared various serotoninergic agents. SSRIs, as a Fluoxetine increased significantly the bleeding time, pharmacological class, doesn’t induce significant effects over

8 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine coagulation from a clinical point of view.

Table 3. Studies included in the systematic review AUTHORS DESIGN RESULTS AND OBSERVATIONS

Reikvam AG, Hustad Case-control pilot study. Donors with SSRIs had significantly lower serotonin in their S, Reikvam H, et al., In vitro measurements of platelet function. thrombocytes. Coagulation could be altered in patients using 2012 [1] N=18. SSRIs based on lower serotonin platelet concentration. Blood donors using SSRIs vs. blood donors without treatment Siddiqui R, Gawande Prospective, open-label, diagnosis of MDD. At week 12 a significant increase in bleeding time was detected S, Shende T, et al., Bleeding time, clotting time, platelet count, for fluoxetine, while escitalopram had no effect on coagulation 2011 [5] prothrombin time, partial thromboplastin kaolin variables. time – all were monitored for 12 weeks. Fluoxetine is more powerful inhibitor of SERT than N=40. escitalopram. Treatment with fluoxetine or escitalopram Fluoxetine increased significantly the bleeding time, but not beyond the normal values Geiser F, Conrad R, Case-control study. Fibrinogen, plasminogen activator inhibitor, PAP differentiated Imbierowicz K, et al., Anxiety and comorbid depression. SSRIs treated patients from their matched controls. 2011 [3] APTT, fibrinogen, factor VII, factor VIII, von After controlling for smoke status and BMI, differences Willebrand factor, von Willebrand ristocetin between groups were significant for PAP, von Willebrand cofactor activity, prothrombin fragment 1 and 2, ristocetin cofactor activity and APTT. thrombin-antithrombin complex, d-dimer, Several coagulation indicators may be affected at significant alpha2-antiplasmin, PAP, tissue plasminogen levels (p<0.05) in anxious-depressive patients treated with activator and plasminogen activator inhibitor. SSRIs N=62. Teichert M, Visser LE, Prospective, populational-based cohort study. The risk for over-anticoagulation during acenocoumarol Uitterlinden AG, et INR≥6 was the event monitored in patients maintenance treatment was increased in patients treated with al., 2011 [7] treated with SSRIs during acenocumarol fluvoxamine, but not with other SSRIs. maintenance treatment. Prothrombine time in users of acenocoumarol was increased N=225 by fluvoxamine above a critical value associated with bleeding Age ≥ 45 risk. Number of exposed patients to other SSRIs except for fluvoxamine was low. Limke KK, Shelton Case report. Increased values of INR that persisted for 7 days. AR, Elliott ES, 2002 Warfarin+fluvoxamine Fluvoxamine inhibits CYP1A2, 2C9, 2C19 and 3A4, while the [8] 79 year old woman metabolism of warfarine involves the same isoenzimes of CYP450. Yap KB, Low ST, 1999 Case report. The interaction between fluvoxamine and warfarin could [9] Warfarin + fluvoxamine. persist for up to 2 weeks after stopping the antidepressant 80 year old woman Shapiro PA, Multicenter, open-label, pilot study. Bleeding time increased in 12 patients, decreased in 4 patients, Lesperance F, MDD patients identified 5 to 30 days after was unchanged in 2 patients, 3 patients withdraw prematurely. Frasure-Smith N et admission for acute MI. No significant changes in coagulation measures. al., 1999 [4] Serial bleeding time determinations. Sertraline seems to be relatively safe in patients after acute MI. N=26 Ford MA, Anderson Open label. No significant differences in mean prothrombine time before ML, Rindone JP, Stable dose of warfarin + fluoxetine. and during fluoxetine administration were detected. Jaskar DW, 1997 [6] Prothrombine time was measured during the 22 Fluoxetine at 20 mg/day doesn’t influence the hypopro- days of the trial. thrombinemic response of warfarin. N=6 Apseloff G, Wilner Non-blinded, randomised, placebo-controlled. Increased prothrombine time significantly during sertraline KD, Gerber N, Healthy male volunteer. versus placebo (p=0.02). After 22 days a significant increase Tremaine LM, 1997 Warfarin+sertraline or placebo. (p=0.02) in unbound warfarine was observed in sertraline vs. [10] N=12 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

Nevertheless, pharmacokinetic interactions between SSRIs statistical analysis. These patients had at least two and anticoagulants are possible, at the plasma protein determinations of INR and platelet count in their charts and binding level and at the CYP450 isoenzymes level, therefore most of them (62%) had at least 3 coagulation indicators monitoring of the main coagulation parameters is recorded. recommended in patients who undergo serotoninergic antidepressant and anticoagulant treatment. Figure 1: Treatment used during anticoagulation therapy

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 Patients received escitalopram (n=11), citalopram (n=2), coagulation variables are detected during combined, SSRIs paroxetine (n=10), sertraline (n=8), fluoxetine (n=8) or and anticoagulant treatment. fluvoxamine (n=3). Methods Figure 2: SSRIs treatment influence over coagulation indicators We analyzed retrospectively charts of all patients evaluated (% of score variation) for depressive disorders during one year in our department (01 January 2017 – 31 December 2017), which had anticoagulant 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, No significant differences (at p<0.05) were detected in any bipolar depression, dysthymia, adjustment disorder with coagulation indicator for SSRIs as a pharmacologic class, as depressive manifestations, mixed anxious-depressive reflected by t test for dependent samples, when platelet disorder. count (p=0.166), INR (p=0.098), APTT (p=0.110), and bleeding time (p=0.102) were analyzed pre-SSRIs Patients diagnosed with comorbid substance related administration and after at least 7 days (mean duration of disorders were excluded from this analysis, and also those SSRIs treatment before hospital discharge was 8.4 days). with mentioned history of non-adherence to their When translated in percentage of absolute values variation, anticoagulation treatment. all SSRIs changes ranged from 5 to 10% in all the monitored Results parameters.

A number of 42 patients, mean age 56.6, 30 female and 12 ANOVA univariate test resulted in F values ranging between male, diagnosed with MDD (n=23), mixed anxious- 1.67 and 1.28, lower than Fcrit, at p<0.05, and η2 varied depressive disorder (n=10), bipolar depression (n=4), between 0.025 and 0.069, which signifies an influence of 2.5- dysthymia and MDD (n=2) and adjustment disorder with 6.9% of the SSRIs agent over INR, APTT, bleeding time, and depressive manifestations (n=3) were included in the platelet count variation during acenocoumarol treatment. A

10 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine post-hoc analysis showed a superior effect over bleeding differences in the clinical domain are not detectable. time for fluvoxamine over escitalopram and sertraline (p=0.043 and 0.46), although the clinical impact of this Disclaimer difference wasn’t relevant. Octavian Vasiliu was speaker for Servier and Bristol-Myers, and participated in clinical trials funded by Janssen Cilag, Astra Zeneca, No significant adverse event in the hematologic area was Otsuka Pharmaceuticals, Sanofi-Aventis, Sunovion Pharmaceuticals. recorded during hospitalization period and mixed (SSRI and anticoagulant) treatment. Ethical considerations All the analyzed medical charts included patients’ informed consent Two cases (one treated with fluvoxamine 150 mg/day and for processing of their personal data for research and educational one who received paroxetine 40 mg/day) registered values purposes. of INR above therapeutic value (5.2 and 6.1, respectively) List of abbreviations after 8 days of treatment, and acenocumarol doses were 5-HTTLPR= Serotonin-transporter-linked polymorphic region adjusted. APTT= Activated partial thromboplastin time APTT= activated partial thromboplastin time, CONCLUSIONS BMI= body mass index DSM= Diagnostic and Statistical Manual of mental Disorders SSRIs had a minor influence over main coagulation ICD= International Classification of Diseases parameters (INR, APTT, platelet count, and bleeding time) INR= International normalized ratio during acenocoumarol treatment in patients with depressive MDD= major depressive disorder disorder and comorbid cardio-vascular or hematologic MI= myocardial infarction diseases. PAP= plasmin-alpha2-antiplasmin complex SERT= serotonin transporter Fluvoxamine has been associated statistically with a lesser SSRI= Selective serotonin reuptake inhibitor safe profile than escitalopram and sertraline, although

References:

1. Reikvam AG, Hustad S, Reikvam H, et al., The effects of selective 74. serotonin reuptake inhibitors on platelet function in whole blood 6. Ford MA, Anderson ML, Rindone JP, Jaskar DW, Lack of effect of and platelet concnetrates. Platelets 2012;23(4):299-308. fluoxetine on the hypoprothrombinemic response of warfarin. J Clin 2. Abdelmalik N, Ruhe HG, Barwari K, et al., Effect of the selective Psychopharmacol 1997;17(2):110-2. serotonin reuptake inhibitor paroxetine on platelet function is 7. Teichert M, Visser LE, Uitterlinden AG et al. Selective serotonin modified by a SLC6A4 serotonin transporter polymorphism. J re-uptake inhibiting antidepressants and the risk of Thromb Haemost 2008;6(12):2168-74. overanticoagulation during acenocoumarol maintenance 3. Geiser F, Conrad R, Imbierowicz K, et al., Coagulation activation treatment. Br J Pharmacol 2011;72(5):798-805. and fibrinolysis impairment are reduced in patients with anxiety and 8. Limke KK, Shelton AR, Elliott ES, Fluvoxamine interaction with depression when medicated with serotoninergic antidepressants. warfarin. Ann Pharmacother 2002;36(12):1890-2. Psychiatry Clin Neurosci 2011;65(5):518-25. 9. Yap KB, Low ST, Interaction of fluvoxamine with warfarin in an 4. Shapiro PA, Lesperance F, Frasure-Smith N, et al., An open-label elderly woman. Singapore Med J 1999;40(7):480-2. preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti- 10. Apseloff G, Wilner KD, Gerber N, Tremaine LM, Effect of Depressant Heart Attack Trial. Am Heart J 1999;137(6):1100-6. sertraline on protein binding of warfarin. Clin Pharmacokinet 1997;32(Suppl.1):37-42. 5. Siddiqui R, Gawande S, Shende T, et al., SSRI-induced coagulopathy: is it really? Ther Adv Psychopharmacol 2011;1(6):169-

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 less tactile real feel, loss of depth understanding, fulcrum effect and also due to manipulation: hand-eye coordination. On a continuous way to become an overall gold standard Young urologists, especially residents, should be better laparascopy and minimally invasive surgery in general shows prepared before performing their first interventions and this better results in terms of patient recovery, hospitalization can be done in a safe, repeatable environment with the help period, and fewer complications such as blood loss or side of medical simulation. effects due to less required analgesia when compared to large open incisions [1]. Minimally invasive surgery also gives Basic and essential skills such as camera manipulation, the advantage of smaller wound infection rates [2], fewer moving objects, manipulating intracorporeal materials (i.e. dehiscence rate and incisional hernia [1]. Key whole surgery gauzes, tissue), knotting and suturing, tissue manipulation requires more time, energy and financial resources. For can be trained using medical simulation. In laparoscopy example, the learning curve for laparoscopic radical medical simulation can be trained with the help of basic prostatectomy was slower than the previously reported pelvic trainers, virtual simulators which can also help learning curves for open surgery [3]. All of these are due to improve procedural steps and live surgery on animal tissue such as porcine models.

1 “Prof. Dr. Theodor Burghele” Clinical Hospital, Bucharest, The most reproducible, accessible and economic way of Romania Corresponding author: Cristian V. Toma MD 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania [email protected]

12 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine teaching laparoscopy to beginners is with pelvic trainers/box study. All of the instructors who were part of the project had trainers. Unlike open surgery where one can encounter to train other senior students or residents with the aim of more learning possibilities, laparoscopic training for young forming bench side instructors who would facilitate the surgeons is a challenge in their formation. communication between participants and main instructor and also give technical and logistic aid to the participants. Training with the help of medical simulation has the purpose to transfer the acquired skills in the operating room [4]. In Tasks order to establish a minimum standard of training the The European training in Basic Laparoscopic Urological Skills European Society of Urology established a model called E- consists of an online theoretical course which is followed by BLUS European Basic Laparoscopic Urologic Skills. realizing 4 tasks in a specific amount of time. The tasks and This model has a set of validated exercises which are their demo version can be found on the uroweb.org website. applicable in urologic laparoscopic procedures. In addition to [7] repeating the video showed skills one can improve the The tasks that were shown to GROUP A were similar to the learning curves by identifying possible factors without taking ones from the E-BLUS. Peg transfer and circle cutting were into account the native ability of the surgeon or his previous identical. Needle guidance was observed in previous surgical experience. [5] “And therefore I find that being a workshops to discourage students due to its difficulty and surgeon is a vocational profession, such as the athletes and high energy consumption so we decided to take a thicker airplane pilots” [6] thus meaning that the surgeon should thread/suture without a needle so it would be easier to also exercise before passing to real life scenarios, exactly manipulate, but maintain the same rotation, piston like and how pilots train on advanced simulators in order to perfect hand eye coordination requirement. The laparoscopic their skills. suturing exercise was divided in two sub-tasks. The first one was to make a laparoscopic intracorporeal surgical knot, OBJECTIVE while the second one required for the volunteers to realize a To assess the better methodology of learning basic urologic surgical knot, make 3 sutures and then close with a second laparoscopic skills by medical students using a box trainer. knot on a silicon model [8].

The methodology for group A was the following: instructor METHODS delivered two 15 minutes presentations on laparoscopy in A study was realized with 54 medical students from all years general and laparoscopic instruments, after these all of the of study from the University of Medicine and Pharmacy procedures were shown one by one by the main instructor “Carol Davila” from Bucharest through from January 2017 to at the demo pelvic trainer and immediately after the November 2018. The participants signed an informed participants repeated each procedure with measuring the consent and completed forms requiring basic demographic initial time and the after 15 minutes training timing. data such as age, year of study, gender, will to pursuit Group B on the other hand repeated the same exercises, surgical careers and dominant hand. received the same live demonstration and video support. In The participants were divided in two groups. Group A had 28 addition to these, each of the exercise except circle cutting students who were trained within 3 separate workshops (10, had a 3 minute training session with different exercises. Peg 9, 9) following one simple metho-dology; group B contained transfer exercise was preceded by lifting 6 pin board pins one 26 participants who were divided in 3 separate workshops by one, passing them from one instrument to the other and (10, 8, 8) and followed a more explicit and didactic placing them in a plastic recipient. The thread passing technique. exercise was preceded by a 3 minutes exercise which required passing of an articulated metal piece through a All of the participants had to do the E-BLUS exercises. The fixed orifice. first time they realized each exercise they were timed and after 15 minutes of practice they repeated the same The breakthrough of this project besides improving the measurement. The selected time was 15 minutes in order to laparoscopic skills of all students was the significant have enough time, energy and concentration for the improvement in time for the knot and suturing part of the students to perform the tasks. workshop for Group B. The participants from Group B were made to repeat the intra-corporeal knot with the The instructors were represented by either urologists or laparoscopic instruments under direct vision after the initial general surgeons with laparoscopic experience. Pedagogical timing was measured. skills of the instructors were a criteria for inclusion in the

This was done by disconnecting the monitor and changing RESULTS the “abdominal wall” from the pelvic trainer with a The average year of study was 3.58, the male-female ratio transparent plastic sheet. In this way the movements were was 1:1.4, and none of them had previous laparscopic maintained restrained by the trocars, but the conversion surgery experience. All of the presented times are median from 2D to 3D natural view was present. scores over the same sector. All of the 28 scores of Peg As a result the students at a cognitive level saw the Transfer Before section were summed and then divided by procedure under 3D circumstances and when conversion to 28. The same principle was applied to all sections. The Time conventional 2D laparoscopic conditions was made the Difference column shows the performance in time before overall final improvement was significant as it will be shown the Group B and Group A. in the results section.

Figure 1: Comparison between groups

As one can see in Table 1 there is no significant difference in natural view and than reproduce the gestures and steps the before timing of the majority of exercises besides combining 3D cognitive perception with 2D laparoscopic knotting and suturing which was enhanced in Group B vision. probably due to the technique of showing the tasks under

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 enhanced abilities given by the two extra exercises. group due to the fact that no extra exercise or technique was The overall extension of the Group B training time given by used in the Group B in order to enhance the performance. the three extra exercises of three minutes each was of nine In group B there was significant difference even in the minutes in practical extra activity and 21 minutes required “before” timing of knots and sutures probably due to the to change the materials within the pelvic trainer.

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

Figure 2: Comparison – linear interpretation

DISCUSSION its role in reducing the necessary time to acquire basic urologic skills in a safe and repeatable environment without The timings could have been improved if the participants the stress and pressure felt in operating room. This study would have had more ergonomic instruments. All of the demonstrates that even simple methodology can enhance instruments had finger rings – Mayo Hegar laparoscopic the beginner’s basic laparoscopic skills. In addition, due to needle holder. experience, medical professional who teach these type of Due to technical possibilities the table on which we placed procedures can accelerate the process with tips and tricks the pelvic trainers had the same height which was which precede the proposed measuring tools. In this way the inappropriate for short or tall students. Step stools were time from transferring the skills from laboratory to the given to short students, but not offering them the best operating room can be shortened and overall confidence of conditions. Tall students had the same problem. the surgeon can be enhanced. The three speakers who took part in this project had two Disclaimer presences- one for group A and one for Group B. The sub- Nothing to declare. No financial grants or other funding were used. instructors were the same along the entire project. Aknowledgements: Medical Simulation Center “LifeSim”, Bucharest CONCLUSION for offering the box trainers and space. It is well known that medical simulation in laparoscopy has

References:

1. Henry MM, Thompson JN. Clinical Surgery. London: W B Saunders, Aug; 146(2):381-6. 2001 6. Mischianu D - Being a surgeon - a terrible and fascinating job – 2. Daniar K.Osmonov et al, Turk J Urol. 2018 Jul; 44(4): 303–310. RJMM, 2018 April, 25(4):3-4 3. Andrew J Vickers et al, Lancet Oncol. 2009 May; 10(5): 475–480 7. http://uroweb.org/education/online-education/surgical- education/laparoscopy/ 4. Bonrath EM, Weber BK, Fritz M, Mees ST, Wolters HH, Senninger N, Rijcken E Surgery. 2012 Jul; 152(1):12-20. 8. https://www.simulab.com/products/tissue-suture-pad- package-0 5. Feldman LS, Cao J, Andalib A, Fraser S, Fried GM Surgery. 2009

Article received on May 6, 2019 and accepted for publishing on June 23, 2019. 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 importance of rotational positioning. They recommended that the tibial component should be aligned with the tibial Total knee arthroplasty (TKA) is an intervention whose tuberosity and the femoral component in a relative external efficacy in the treatment of gonarthrosis is well known and rotation to the tibia at the time of a complete extension [3]. documented [1]. The results of this intervention depend on the correct positioning of the prosthetic components in all Femoral component positioning errors in the axial plane lead three planes: frontal, sagittal, and axial [2]. The axial plane to complications in the femuropatellar joint, ligament within TKA is represented by the alignment of the prosthetic instability and changes in normal kinematics [4]. The components in the rotational plane. In 1979, Mochizuki and positioning of the tibial component from a rotational point Schurman, who have shown that a lateral force produces the of view has not been as studied, but its importance is equally sprain of the patella when the tibial component is positioned large. The malposition of the tibial component is indirectly according to the posterior plateau, described the responsible for the femuropatellar complications that are often the cause of postoperative knee pain, reduced mobility 1 “Carol Davila” University of Medicine and Pharmacy, Bucharest, and early revision [5]. Although current instrumentation Romania methods have greatly reduced the malposition rate of 2 Department of Orthopedics and Traumatology, University Emergency Hospital, Bucharest, Romania Corresponding author: Bogdan Cretu, MD 3 Department of Orthopedics and Traumatology, Pantelimon Emergency Hospital, Bucharest, Romania [email protected]

16 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine components, the subject of rotation is not a closed one, and tension both internally and externally and, after creating the there is no consensus for the perfect positioning. posterior femoral cuts, the posterior femur should be parallel to the tibial surface after proximal tibial resection so In this paper, we will try to present a review of recent that this space is rectangular. To support this theory, Laskin literature on the correct rotational positioning of the compared two groups of patients, in one group, the size of femoral and tibial component, to describe the different axes posterior femoral cuts was equal, and in the second group, guiding the rotational alignment, and to compare the known the resection plane of posterior condyles was externally techniques. rotated to obtain a rectangular space. He noted that for this, it is necessary that the posterior medial femoral cut is larger ROTATION OF FEMORAL COMPONENT than the lateral one, with a relative increase of this The correct positioning of the femoral component from a difference in the valgus knees due to lateral femoral rotational point of view is an important step for the success condylar hypoplasia. The average external rotation for of TKA. The positioning of the femoral component in axial flexion space rectangulation was 3.20 to the posterior plane has repercussions on stability in flexion, knee condylar line [14]. kinematics, flexion alignment and femuropatellar joint [6, 7]. Correct valgus or varus extension positioning is a problem Berger demonstrated the relationship between the internal solved by current instrumentation systems but varus or rotation of the femoral component and the patellar valgus flexion alignment is often forgotten. This problem was maltracking [8]. He was the first to use the CT to evaluate the investigated in a cadaver study, in which they compared the rotation of prosthetic components. He showed that a low “tension gap” technique with the anteroposterior axis internal rotation, between 1 and 4o would lead to patellar (Whiteside’s Line). Using the “tension gap” technique, they maltracking and tilting, an average internal rotation, noted that they had good stability in extension and flexion, between 5 and 8o would lead to subluxation and a severe but the knees had varus deviations at flexion with an average internal rotation of 7-17o, would lead to the sprain of the of 8.2 , increasing pressure in the internal compartment. patella. For the analysis of both femoral and tibial rotation, This phenomenon is largely due to the lateral collateral Berger used the transepicondylar axis (TEA) and tibial ligament, which in a normal knee is slightly laxer than the tuberosity as anatomical landmark. medial, this allowing the tibia to be pushed into varus The external rotation of the femoral component also has (allowing the internal rotation of the femur against the tibia) negative repercussions on the TKA. Olcott et al. have shown when using the tensioning methods of equalizing the that with the increase of external rotation of the femoral tensions between the two ligaments [15]. In the group in component, the medial flexion space increases, the result which the antero-posterior axis was used, the results were being a flexion instability symptomatology [9]. Another better in terms of stability and alignment. study led by Hanada et al. has shown that the excessive Transepicondylar axis (TEA) external rotation of the femur leads to varus flexion, the result being an excessive loading of the external It is defined as a line crossing the two epicondyles, medial compartment [10]. and lateral. This approximates the flexion-extension axis of the knee [16]. The positioning of the femoral component in The consequences of external femoral rotation are well the axial plane according to this line leads to an optimal known; the best landmark for a good rotation is a topic yet patellar tracking, decreases the shearing forces at the debated. Many landmarks and axes have been described at beginning of flexion, and decreases the use of polyethylene the level of distal femur: posterior condylar line (PCL), insert. Internal or external rotations to this axis will result in transepicondylar axis (TEA), surgical transepicondylar axis changes in the patellar tracking [17]. The defect of this axis (sTEA), anteroposterior axis (AP) or Whiteside line anterior is that it cannot be located accurately intraoperatively. femoral axis [11, 12]. Berger et al. examined the knees of 75 cadavers and came to “Tension gap” technique the following conclusions: surgical TEA is the axis between the lateral epicondyle and the medial sulcus, a channel The purpose of this technique is that after creating the gaps, below the medial epicondyle [18]. They concluded that the the flexion space should be rectangular and equal to the medial sulcus was an easily identifiable anatomical landmark extension space [13]. The soft parts of the knee are first and measured the difference between surgical TEA and the balanced in complete extension by ligament rebalancing and posterior condylar line as being 3.5○ in males and 0.3○ in subsequently at 90o flexion, either manually or with a females. After studying 32 cadavers, Yoshioka et al. laminar spreader. The aim is to obtain equal ligament concluded that there is a “condylar twist angle” of 5○ in

males and of 6○ in females [19]. Although TEA is an axis we know that higher revision rates occur, and the clinical difficult to highlight during surgery, especially in cases of results are weaker at the time of malposition of the tibial significant destructive changes or in revisions, it could be the component [23]. Many intra- and extra-articular landmarks most accurate landmark for determining the rotation of the are known. Intra-articular landmarks are tibial tuberosity, femoral component. patellar ligament, and posterior tibial axis. There is also an option of alignment with the femoral component implanted Posterior condylar line (PCL) according to TEA in extension [24]. Another option is to place Using the posterior condylar line as a landmark for the tibial component so that we have maximum tibial determining the femoral rotation is a well-known and coverage [25]. The extra-articular landmarks are the generally accepted technique. PCL is on average 3-5○ in transmalleolar axis of the ankle and the metatarsal II axis. internal rotation than TEA [20]. Most of the TKA instruments The decision regarding what type of landmark to use for the kits have additional pieces for external rotation attached to axial alignment of the tibia is a difficult one and is influenced the instrument that palpates the posterior condyles, which by other intraoperative factors. The external rotation of the try to position the two pins of the femoral cutting block plateau increases when an external parapatellar approach is parallel to TEA. In examination, PCL is identified by used and an incomplete tibial plateau exposure resulting in digitization and the desired external rotation is added to it. internal rotation of the plateau [26].

Different studies highlighted that optimal patellar tracking Finding the optimal rotation of the tibial plateau requires a was obtained with external rotation of the femoral deep understanding of knee kinematics. In a normal knee, component. Patients with the femoral component in the tibia makes an internal rotation motion at the time the external rotation do not need a rebalance of the extensor knee is in flexion and an external rotation motion at the end retinaculum and have better postoperative patellar tracking. of the extension. This mechanism of external rotation at the This classic technique of positioning the femoral component end of the extension is called “screw home mechanism”, due in external rotation is easy to use but has the disadvantage to the geometry of the joint surfaces combined with the that posterior condyles have to be perfectly palpated. This is cruciate ligaments [27]. not always possible due to the size differences of posterior This physiological movement occurs between 0 and 15○ of condyles especially in cases of genu valgus with lateral flexion. Often, this mechanism sometimes disappears, is low femoral condylar hypoplasia in which there is a risk of or paradoxically appears after TKA [28]. To reduce internal rotation of the femoral component. polyethylene use, we need to obtain a better axing of the Trochlear anteroposterior (AP) axis two components in axial plane after TKA. The aim is to have a neutral rotation between the two components during the Also called the Whiteside line, the trochlear anteroposterior entire flexion, the rotational gap leading to femorotibial (AP) axis was originally described as a landmark in subluxation and early destruction of the polyethylene unicompartmental arthroplasty [21]. It was later used as a insertion. landmark for the positioning of the femoral component in axial plane in valgus deviation knees. It is defined as a line Extra-articular landmarks that joins the deepest point of femoral trochlea with the The most known extra-articular anatomic landmarks for center of the deep lateral femoral notch. The perpendicular rotation positioning of the tibial component are the line on the AP axis is about 4○ of external rotation compared transmalleolar axis of the ankle and the metatarsal II axis. to PCL. TEA has an average of 4.4○ of external rotation Both axes have a significant variability in their knee compared with AP axis. The AP axis has the advantage of orientation in different individuals [29]. In conclusion, these being easy to use and it can be identified during basic TKA. landmarks should not be the only ones used to determine the rotation. Extra-articular deformities secondary to TIBIAL COMPONENT ROTATION trauma or arthrosis may result in alteration of these The tibial component rotation is at least as important as the landmarks relative to the knee [30]. rotation of femoral component. The positioning of the tibial Intra-articular landmarks component in axial plane is responsible for optimal patellar tracking. An internal rotation will lead to a lateralization of Anterior tibial tuberosity is the most commonly used tibial tuberosity and an increase of Q angle that will anatomical landmark for the proper determination of tibial predispose to the subluxation of the patella [22]. The plateau rotation. It is a landmark easy to identify and is not optimal tibial component position is not known exactly but modified by gonarthrosis. This anatomical structure was split

18 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine to increase the efficiency of its identification and its use. To “Self-seeking” method determine the rotation, the internal edge of the tuberosity This method involves introducing trial components and and 1/3 of the internal tuberosity are used [30]. performing full flexion and complete extension. The trial In a study using the CT, the medial edge of the tuberosity was tibial plateau will be rotationally positioned according to the used in a lot of patients and in the second lot of patients, 1/3 femoral component. The center of the trial tibial component of the internal tuberosity was used for the positioning of the is marked with the electrocautery and the final implantation tibial plateau in axial plane. The femoral component in all is made using this point as landmark. This technique depends patients was positioned according to TEA. In the lot of on the correct positioning of the femoral component, in patients in which 1/3 of the internal tuberosity was used as femoral malrotation, the tibial component will also be landmark, the femorotibial gap was lower, 67.5% of the affected. There is a risk that, when the femoral component patients between ±5○, 85% between ±10○ and 97.5% is positioned in internal rotation and the tibial plateau is between ±20○, compared to the lot of patients in which the internally rotated, major problems of patellar tracking occur medial edge of tuberosity was used, 3.8% of the patients together with an increased instability. In order to overcome between ±5○, 15% between ±10○ and 68.8% between ±20○. this problem and at the same time to use it, it is In conclusion, the authors support the use of 1/3 of the recommended to use a mobile plateau that will rebalance internal tuberosity as landmark for the positioning of the the tibiofemoral gap. tibial plateau [31]. The mobile tibial plateau or “mobile-bearing” was built so Another study evaluated the relationship between TEA, the that the polyethylene insertion follows the femoral patellar ligament, and the posterior tibial axis in 30 healthy component in rotation and the tibial component in flexion- patients by MRI [32]. They found that the perpendicular line extension. “Mobile-bearing” TKA reduces the need for tibial on TEA intersects the middle of the patellar ligament, the component placing in a perfect rotation and reduces the gap intersection being at about 41% of the width of the tendon between the tibia and the femur. The disadvantage is that a measured from its internal edge. In order to have a smaller second joint surface is created between the insertion and gap between the femur and the tibia, the anteroposterior the tibial plateau and the destruction of polyethylene can axis of the tibial component must intersect the patellar occur at both interfaces. ligament and the femoral component aligned with the TEA. This technique will finally result in a lack of coverage of the CONCLUSIONS posteromedial tibia of about 5 mm with a variation between TKA function and survival depend on an optimal rotation of 2 and 10 mm. The patellar ligament is not modified by the femoral component but also of the tibial component. gonarthrosis, but its width is variable depending on the The positioning of the femoral and tibial component is well surgical approach. When the tibial plateau is positioned known in the sagittal and frontal plane, but it is not very clear depending on the posterior cortex, it will enlarge the tibia in the axial plane. There is a consensus that the femur should coverage, but will also greatly raise the rate of the internal be positioned according to TEA but the methods this would rotation of the tibial plateau. The authors of the study be possible are not optimal. The combination of different concluded that the optimal landmark is an immediate point techniques and the use of many landmarks could be a located medial to the patellar ligament. The normal solution. The rotation of the tibial component remains an anteroposterior diameter of the tibial plateaus is different, open subject, most studies suggesting a point between half and this will lead to the highlighting of the posteromedial of the distance of patellar ligament and 1/3 of the internal bone at the time the tibial plateau is positioned correctly. tuberosity as optimal landmark.

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6. Oussedik S, Scholes C, Ferguson D, Roe J, Parker D. Is femoral aligned" total knee arthroplasty to the posterior condylar, component rotation in a TKA reliably guided by the functional transepicondylar, and anteroposterior femoral axes. Knee. 2014 flexion axis? Clin Orthop Relat Res. 2012 Nov;470(11):3227-32. doi: Dec;21(6):1120-3. doi: 10.1016/j.knee.2014.07.025. Epub 2014 Jul 10.1007/s11999-012-2515-0. Epub 2012 Aug 16. 25. 7. Churchill JL, Khlopas A, Sultan AA, Harwin SF, Mont MA. Gap- 21. Whiteside LA, Kasselt MR, Haynes DW. Varus-valgus and Balancing versus Measured Resection Technique in Total Knee rotational stability in rotationally unconstrained total knee Arthroplasty: A Comparison Study. J Knee Surg. 2018 Jan;31(1):13- arthroplasty. Clin Orthop Relat Res. 1987.219: 147-57 16. doi: 10.1055/s-0037-1608820. Epub 2017 Nov 27. 22. Nedopil AJ, Howell SM, Hull ML. Does Malrotation of the Tibial 8. Berger RA, Rubash HE, Seel MU, et al. 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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 b) Attracting the attention of domestic and international public opinion to the "noble goal" pursued. The biological attack is the artificial spread by various means of pathogens that can cause serious infectious and c) Undermining the authority of political regimes in some contagious diseases as well as the spread of germ toxins that countries by creating a state of inner strain, insecurity and can be used by an aggressor as a means of fighting in order uncertainty, economic and social chaos. to reduce the troops’ fighting force, by causing serious d) Forcing authorities to meet certain requests. disease outbreaks or by killing people, animals and/or plants. g) Revenge on some officials. Biological agents are microorganisms and/or microbial, animal or plant toxins, used as specific ammunition for h) Achieving military goals: management disruption at a biological weapons or used by terrorists in "bio-chem" strategic or operational level, diminishing or partially attacks. destroying the opponent's military potential, the disruption of the logistics system, paralyzing communications and Terrorism, according to the League of Nations (1937), can be telecommunication systems. 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 1 general public. The Military-Medical Institute, Bucharest, Romania 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, The objectives of terrorism can be grouped as follows: Romania 3 Military Medical Research Center, Bucharest, Romania a) Achieving political goals. 4 “Titu Maiorescu” University, Bucharest, Romania

i) Religious fanaticism. zooanthroponoses, affecting both animals and humans alike. [1, 2]. Bioterrorism consists in using or threatening to use the weapon of mass destruction for claims, with the declared BRIEF HISTORY intent of affecting the public health and/or the environment. "Read the history and, thus, discover what will be" Nicolae Currently, the following means are known for dispersing Iorga rightly said. The first "chemical weapons" - "toxic biological agents: smoke" were used around 424 BC in the Peloponnesian War. - Using saboteurs; The first users of the "biological weapon" (around 400 BC) - Using vectors of microorganisms such as insects, mites, can be considered the Scythians, who used arrows soaked in rodents or other infected animals; decomposing bodies or mixed with manure. The Spartans - Incorporation of biological agents into explosive ammuni- used to cast sieves of sulfur-moistened wood on sieged tion; fortresses. Greek, Persian, and Roman literatures describe - Aerosolization – through aerosols released from the how dead animals were used for fountain-contaminate. ground, air or sea – is considered the most effective means of contaminating large areas of territory within the shortest The Mongols, in the siege of the Kaffa fortress in Crimea, feasible time interval. during the war waged between 1346 and 1347, used the corpses of those killed by the plague in order to infect or With regard to the production of biological weapons, both create a breach among the fortress defenders. ordinary and resistant biological agents can be used, the latter being preferred, because they cause a form of the In the fifteenth century, the Spanish infested the French disease that can not be treated with the usual drugs, causing wine with blood from those infected with the pests. Also, at a disease outbreak of greater magnitude and severity. that time, Pizzaro distributed to the Americans in South America garments contaminated with smallpox. In the In general, biological attacks are masked by natural sixteenth century, the same virus was used by the English to epidemics, epizooties and epiphytosis, the latter two being impregnate the blankets distributed to the ameridian tribes generally considered to be economic attacks, with the aim of that helped the French. In the war against Sweden in 1710, decreasing trade, implicitly, causing the decline of the the Russian troops used the same method as the Tartar army standard of living in the affected area. did 400 years prior – namely, the use of the corpses of those Biological attacks can also be manifested in the form of 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)

Category TOTAL No Objectives Comments Terrorist Criminal Others/not specified cases 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 The Comments The most fewest

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

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

Category TOTAL No Activity Comments Terrorist Criminal Others/not specified cases 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 The Comments The most fewest

During the Vietnam War, Americans used defoliant, Tom Brokaw from NBC News, as well as by the newspaper desiccant and sterilizing herbicides. These substances did "The New York Post ". On November 2nd, 2001, a letter not fall under the Geneva Protocol of 1925 nor in the containing anthrax spores was found in Karachi, Pakistan, Convention on the Prohibition of Chemical Weapons. In the which was addressed to the newspaper "Daily Jang". In 1970s, ricin was used to assassinate Bulgarian dissidents Santiago, a similar postal mailing resulted in disease Gheorghe Markov and Vladimir Kostov. outbreaks of thirteen people.

In 1976, the mayors of several US cities were the recipients Figure 1. Frequency of the illicit use of biological agents in the of letters that were delivered in envelopes on which had 20th century, on decades (W. S. Carus) [α] 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, After September 11, 2001, the danger of massive terrorist predominantly children and women. Also in 1995, Iraq attacks on the population of any part of the world is no admitted to having in its posession Bacillus anthracis, longer just a working hypothesis. Chemical, biological or botulinum toxin and aflatoxins, declaring to be ready to use nuclear terrorism is, at present, one of the most serious them. All this demonstrates that, although the Convention threats to all states. Given the trend of interethnic and on the Prohibition of Chemical Weapons was signed in 1972, religious violence, as well as the number of cases of human the biological weapons research continued. rights violations in certain "high-risk" areas around the globe, analysts have warned against accentuating the risk of Since the end of 1992, there have been many more complex using these types of weapons in terrorist actions, underlining epidemics in the US, Milwaukee area, with wide-ranging the imperative nature of urgently establishing non- effects: 400,000 cases of crypto-sporidium outbreaks from proliferation measures. water consumption; in the spring of 1993, a respiratory epidemic with unidentified causes; during the fall of 1994, Table 3. Type of biological agent used (W.S. Carus) [α] 250,000 cases of salmonella food poisoning. 1 Living agents 136 cases On October 5th, 2001, in the US, Florida area, after having 2 Toxins 26 cases inhaled the anthrax bacillus, a tabloid’s editor passed away. 3 Unknown 6 cases On October 20th, 2001, three letters containing anthrax spores were delivered to Washington DC, USA, having been TOTAL 168 cases received by Tom Daschle, a member of the Senate, and by

COUNTERMEASURES the National Defense System, local communities and non- governmental organizations is crucial in the fight against Combating bioterrorist attacks involves, first of all, the these attacks. These non-medical contermeasures have an intervention of the secret services, the police and the judicial active, prophylactic role, preparing the population in the system. Also, the intervention of the National Health System, event of an attack. [3, 4, 5]

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

Category TOTAL No Dissemination Comments Terrorist Criminal Others/not specified cases

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 The Comments The most fewest

The responsibility for coordinating actions in these situations If we make a retrospective of the 20th century, the most lies with the government of the country holding the EU warrior of all, it is noticed that the practical use of Presidency, with the government of the country under weapons/biological agents was a reality. [6] attack and/or with the European Center for Infectious Disease Control. It is noted that in the last decade of the 20th century there were more cases than in the rest of the century. The specific capabilities of the Medical Department of the Ministry of Defense are important for the medical protection OBSERVATION against weapons of mass destruction and, in particular, for the fight against biological attacks. The Center for Military An important component in the fight against biological Medical Scientific Research has a Laboratory of Anti- attacks is represented by medical espionage, a constantly infective Medical Protection and Epidemiological updated data base of new agents and existing diseases, thus, Emergencies, which functions as a specialized medical becoming the key to finding the most effective treatment. protection unit against biological weapons. It conducts With regard to the measures required for the imminence of military medical scientific research to protect troops and the a biological attack, individual protection means are used civilian population against biological weapons and/or toxins, such as the gas mask - which is not 100% effective, but it for biological warfare, bioterrorist attacks, or biological decreases the amount of inhaled substance, having a accidents. protective role, because for most substances in order for harmfull effects to hapen it is necessary for large quantities Table 5. The mortality rate in the attack with biological agents to be inhaled. (W.S. Carus) [α] Purpose Cases Deaths Chemotherapics present much wider benefits in regards to the protection against biological weapons, acting switftly, 1 Bioterrorism 751 0 having a broad spectrum and being easily administered in 2 Biocrime 130 10 large communities. TOTAL 881 10 Also, a very impressive step after a biological attack is the Source: Carus W. S. „Bioterrorism and Biocrimes. The illicit use of biological agents since 1990”, Center for Counterproliferation Research, National decontamination by appropriate physical and chemical Defense University, Washington DC, 2001. [6] means for the equipment, rooms, clothes, water sources,

24 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine soil, etc. [7, 8, 9, 10] It is necessary to implement preventive measures on the unlawful use of biological agents. Early medical and non- CONCLUSIONS medical countermeasures must be prepared for the prophylaxis, treatment and cessation of the consequences of The risks of bioterrorism and biocrime attacks in the any biological attack. contemporary world are real, and the history of the 20th century and the beginning of the 21st century confirms this.

References:

1. Ordeanu V., Andrieș A., Hîncu L., Microbiologie și protecție TUDOSIE, Colonel (r.) Viorel ORDEANU „Riscul de atatc bioterorist și medicală contra armelor biologice, Editura Universitară „Carol de biocrimă în lumea contemporană”, comunicare Conferința Davila” București, 2008. anuală SUUMC București, sept. 2018 2. Păun, Ludovic, Bioterorismul şi armele biologice, Editura 8. Ionescu LE, Ordeanu V, Dogaru M, Necsulescu M, Popescu DM, Amaltea, 2003; Bicheru SM, Dumitrescu GV. „Research for the development of 3. *** S.R.I., Centrul de informare pentru Cultura de Securitate, logistics planning information support in health protection against Centrul de Cooperare Operativă Antiterorista, Inamicul invizibil. biological agents”, Romaniam Journal of Military Medicine, vol. 121, Bioterorismul și armele biologice în lume, www.sri.ro no. 1/2018, p. 36-39 4. Chiş, Ioan, Popa, Cristina, Terorismul contemporan –fenomen şi 9. Ordeanu V, Necsulescu M, Popescu DM, Ionescu LE, Bicheru SM, infracţiune, Editura A.N.I, Bucureşti, 2007 Dumitrescu GV., Corlan G. „The concept of operationalization of an integrated platform for scientific research and expertise of war end

5. Tun-Comşa, Cristian, Consideraţii privind terorismul bioterrorism biological agents” Romaniam Journal of Military contemporan, www.actrus.ro Medicine, vol. 120, no. 2/2018, p.9-15

6. Carus W. S. „Bioterorism and Biocrimes. The illicit use of 10. Popescu DM, Necsulescu M, Popescu DM, Ionescu LE, Bicheru biological agents since 1990”, Center for Conterproliferation SM, Dumitrescu GV., Ordeanu V. „Capabilities for identification and Research, National Defense University, Washington DC, 2001. confirmation of baterial biological agents” Romaniam Journal of 7. Ioana-Alexandra GAL, Teodora Bianca EREMIA, Mihail Silviu Military Medicine, vol. 119, no. 3/2016, p. 5-9

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 contagious diseases as well as the spread of germ toxins that can be used by an aggressor as a means of fighting in order In the current military-political context, with the Cold War to reduce the troops’ fighting force, by causing serious having ended (1947-1990), we find ourselves in full anti- disease outbreaks or by killing people, animals and/or plants. terror war (since 2001), in which Romania is a direct participant, as a member of NATO and the EU, and the issue Weapons of mass destruction (WMD) are those weapons, of biological warfare and bioterrorism is again highly topical which, used by the aggressor, cause extensive material but bearing other valences. damage (destruction of buildings, constructions, machinery, installations, means of transport, etc.) as well as a large DEFINITIONS number of victims among employees and unprotected War is a short or lasting conflict (whether military or not, animals. declared or not), between two or more groups, social Chemical, biological, radiological and nuclear defence (CBRN categories or countries, aiming to achieve financial, ethnic, defence) represents the protection measures taken during territorial, economic and political interests. times of war or terrorist attacks, in the event of a chemical, The biological warfare is the artificial spread by various biological or nuclear attack. means of pathogens that can cause serious infectious and The biological weapon is a system of unconventional weapons of mass destruction, whose ammunition carries 1 The Military-Medical Institute, Bucharest, Romania biological agents and contaminates the enemy in order to 2 “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania cause disease outbreaks for the latter. 3 Military Medical Research Center, Bucharest, Romania Biological agents are microorganisms and/or microbial, 4 “Titu Maiorescu” University, Bucharest, Romania

26 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine animal or plant toxins, used as specific ammunition for massively released into the area by the enemy and can biological weapons or used by terrorists in "bio-chem" contaminate a large number of humans and/or animals attacks. (anthroposoonosis) turning them into secondary sources of infection by releasing in their turn pathogens in the external Total war is a large-scale conflict in which policy makers environment. Except for those destined exclusively for mobilize all available resources to ensure the destruction of humans and for those common to both humans and animals, the rivals' ability to defend itself. During times of total war, there are also those biological agents destined exclusively there are no actual non-combatants, meaning that all people for the destruction of domestic animals and cultivated in a particular country - civilians and military alike – are plants. considered targets.

The hybrid war represents undeclared wars by those THE PROVISIONS OF INTERNATIONAL LAW participating states, where the military component is not From the point of view of International Law, biological explicitly assumed and is by no means singular (they are weapons are expressely prohibited because they fall under executed in concert as part of a flexible strategy with long- the mass destruction weapons category, and their effect term goals). cannot be limited in time and space, with medium-term effects not always predictable. Moreover, the military use of THE BIOLOGICAL ATTACK biological weapons is currently considered to be tactically Under the conditions of modern warfare, the effects of using and operationally inefficient, being tactically difficult and the biological weapon can be amplified by successive or risky from a medical point of view, because an outbreak once concurrent use with other WMDs. In a concrete battlefield, released can get out of hand. the biological attack can occur with: Exceptions on using WMD a) The enemy on the offensive – can use the biological An important issue in controlling the Convention’s weapon to weaken the opponent's defence power. The most implementation is the existence of certain exceptions likely objectives to be attacked with biological agents would because the Convention cannot completely ban the use of be: living agents and their toxins. So far, no convention banning 1. Concentration of troops, resistance points the use of a certain type of weapon against the enemy has 2. Reserve and support units explicitly prohibited its use on its own population. 3. Air and sea troops found at bridge ends, traffic routes clogs, operational reserves, etc. First of all, biological agents and some toxins can be used in vaccine manufacturing, for diagnostic and treatment In the tactical and operative space, pathogens of diseases of purposes. For example, biological agents may be used in the short and virulent incubation, but non-transmissible from treatment of inflammatory bowel diseases such as Crohn's human to human, will be used. Infected animals or insects disease inflammatory form with moderate or severe activity will not be used, as they would be dangerous for own troops. that have not responded to conventional immune- In the strategic space, the aggressor will spread biological suppressive therapy or where immunosuppressant therapy agents that cause many types of diseases to disrupt the is contraindicated. They may also be used in patients with battlefield, cause panic and aggravate material insurance. moderate/severe RCUH who have not responded to corticosteroid and immunosuppressive therapy or severe/ b) The enemy on defence – could use the biological weapon fulminant colitis. These patients are required to undergo against opposing troop concentrations to reduce their force treatment with drugs such as Infliximab or Adalimumab of attack. Can be attacked with biological agents, the units in containing a chimeric anti-TNFα agent consisting of IgG1 the offensive, those in the second line or the back-ups, the monoclonal antibodies, 25% murine and 75% human, foreign military bases, etc. respectively a fully humanized anti-TNFα agent, IgG1 type. In the operative space, infected insects and animals may also At the same time, the emergence of vaccines has greatly be used to target troop concentrations; the passes, roads, revolutionized medical science since they carry an important and crossing points may be contaminated to hinder the prophylactic role. pursuit. The vaccine is a biological product containing suspensions Living organisms are the sole targets of these attacks, thus (antigens) of attenuated, inactivated (killed) viruses or living buildings (for e.g.) being left intact, these being able to be bacteria, or fractions thereof, which are administered in decontaminated and further used. The biological agent is

order to induce a specific immune response. Depending on PREVENTION OF BIOTERRORISM ATTACKS the type of vaccine, fragments of pathogen agents were used Preventing bioterrorist attacks is mainly a political and social differently: problem, which is primarily achieved through the 1. Viral vaccines – corpuscular vaccines with living intervention of the secret services, police and the justice attenuated viruses (oral polio vaccine, rotavirus vaccine, system. Combating bioterrorist attacks also involves the measles, rubella, varicella, amaryllis) or inactivated viruses intervention of the National Health System, the National (inactivated polio vaccine, rabies, Hep A) and antigenic Defence System, etc. The specific capacities of the Medical fragments or viral subunits (Hep B, influenza vaccine) Department of the Ministry of Defence are important for the medical protection against the weapons of mass destruction 2. Bacterial-corpuscular vaccines with living attenua-ted and especially for fighting against biological attacks, germs (BCG) or killed (germs), (cholera vaccine, pertussis), permanently having the forces and means necessary for the polysaccharide subunits (meningococcal, pneumococcal, medical protection against the C.B.R.N agents. Hib, typhoid vaccine) or purified (pertussis acelular) The Center for Military Medicine Scientific Research 3. Anatoxin – diphtheria, tetanus (CCSMM) has a Laboratory of Anti-infective Medical Thus, the BTWC allows all signatory countries to possess and Protection and Epidemiological Emergencies, which use reasonably small (grams) quantities of BWA for functions as a specialized medical protection unit against defensive scientific research to obtain new means of biological weapons. It conducts military medical scientific diagnosis, prophylaxis and treatment. But a real problem is research to protect troops and the civilian population that these living biological agents can be multiplied on against biological weapons and/or toxins, for biological demand and in any quantity or can synthesize toxins as warfare events, bioterrorist attacks, or biological accidents specific ammunition for biological weapons. targeting primarily: bacteria, viruses, fungi, etc. and their toxins, to establish medical protection procedures, through Secondly, one of the BTWC articles states that in case of cooperation between different medical specialties: force majeure, when a state itself is threatened, it may notify microbiology, epidemiology, etc. the UN three months before resuming the production of biological weapons to deter the enemy. This also explains A first stage subsequent to the occurrence of a biological why Israel, "an island in a sea of hostile Arabs", has not attack is the identification of the causal agent, being signed and ratified the convention. performed solely in a microbiology laboratory, starting from correctly harvested samples (from the air, soil, water, And Romania, which joined since 1972, ratified it only in pathological products from the sick, etc.). The identification 1979, in order to have an extra advantage in the face of a operation must be quick and specific. possible assault of the USSR in the context after 1968. It should be underlined that in fact Romania has not In the event of an immediate biological attack, the problem researched, manufactured, stored, and has never used at hand is the immediate decontamination by appropriate biological or toxin weapons, nor did it have such an physical and chemical means of the staff’s equipment, of the intention, but it was indeed, the target of covert biological rooms, the water sources and the food, etc. The appropriate attacks in the 20th century and, we must continue to take anti-epidemic measures to limit the spread of the infection preventive measures. are, along with the above, another important stage in the post-attack protocol, in which we will: isolate the sick and In this complex situation, effective legal measures for the the suspects, take care of individual and collective hygiene, application of the BTWC need to be implemented qarantine the D.D.D. actions and so on. If the agent has been worldwide, but concrete actions are difficult to apply in identified, we can perform emergency immunoprophylaxis practice. The UN is in a position, as an international forum, by using vaccines, by administering prophylactic or to impose and control compliance with the Convention, therapeutic antibiotics, etc. being helped by the Security Council, the World Health Organization as a specialized body. The protection against biological attacks depends on the moment when the attack is detected, thus, when the media STANAG are NATO standards for different areas that set shall signal the imminence of an attack, the possibility to technical or operational standards in certain situations, benefit from individual protection (ex-gas mask) and including in the field of biological warfare, and which need collective protective means (shelters) should be available. to be adapted and implemented by Allied countries for The biological means of protection and the emergency interoperability. prophylaxis with appropriate substances (serums, vaccines,

28 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine etc.) can be of good efficacy. Immunostimulators and carried out, with only little evidence on the existence of such chemo-therapeutic agents (wide-spectrum antimicrobials) programs in the current media. Specific anti-human, anti- can also be associated with these. animal and anti-plant programs have been developed, agents have been standardized for use as weapons, and THE BIOLOGICAL WARFARE – A HISTORICAL REVIEW insects have been studied for use as natural dispersion vectors. There are very few data from the Prehistory and Antiquity that testify to the use of biological weapons during warfare. PERSPECTIVES However, the latest research attests to the fact that the Hittites were the pioneers of bioterrorism. The Hittite people The range of pathogens used as biological weapons is very lived on a territory that today belongs mostly to Turkey. wide, which gives rise to particular difficulties in the Three thousand years ago, they used infected sheep aiming elaboration of the protection and treatment measures. at conquering enemy people. According to the study Types of agents: performed by the Italian microbiologist Siro Trevisanato, the 1. Bacteria: anthrax, plague, cholera etc; bacterium considered the first weapon of mass destruction 2. Viruses: yellow fever, tick-borne encephalitis (TBE), in history was Francisella Tularensis, responsible for smallpox, etc; tularemia, an infectious and contagious rodent disease, 3. Rickettsia: Q fever, exanthema of typhus etc; caused by a bacterium and transmitted to domestic animals 4. Pathogenic fungi: coccidioidoreo etiological agents, etc; and humans, manifesting itself by fever, chills, vomiting, etc. 5. Toxins: bacterial (Botulinum, staphylococcal, etc.), fungal, The disease still exists nowadays and, if not treated properly, of animals or plants (ricinotoxin). can lead to death. Studying ancient papers, researchers have These are only the pathogens found in nature. But new proven that tularemia first appeared in a Phoenician city genetic techniques now allow us to obtain germs with new (located on the border between Lebanon and Syria today) in qualities, not naturally occurring (modified or hybridized) the Middle East in the 14th century BC. The Hittites and which can be considered more dangerous by their plundered this city in 1325, bringing with them infected pathogenic effect and increased resistance in the external animals, which may have spread the disease – also referred environment. to as the "Hittite Plague" - throughout its territory, as explained by the researcher. Trevisanato points out that Some agents have a lethal effect, while others have an there are several papers attesting the epidemic. At the time incapacitating effect, leaving man out for a period of time of tularemia’s utter virulence, the Hittites came to the ranging from a few hours to a few weeks. attention of a neighboring population of the city of Arzawa They can be joined by immunosuppressive substances, (Western Anatolia), who took advantage of their weakness which disrupt the mechanisms of the body's anti-infectious to invade their territory. resistance, exposing it to current infections or to those During the Middle Age as a Mongol saw his comrades die of deliberately disseminated. plague in the three years of the siege of Caffa's Black Sea city, In the case of a biological attack, it should be stressed that founded by the Genovese, he had the brilliant idea of the possibility of using two or more biological agents throwing corpses over the city walls. The Genoese left the simultaneously, whose effects combine or potentiate, or can city, but the plague spread across Europe. be used with other weapons of mass destruction, is In the Modern Age – the First World War brought a more estimated. sophisticated biological warfare, with the development of We can also mention the existence of biological agents microbiology, many pathogens causing diseases could be destined exclusively for destroying domestic animals and identified that could then be cultivated in the laboratory. cultivated plants (e.g. avian influenza, barberry rust for There are suspicions about the use of plague against Russian plants) that can lead to large losses or can be used to destroy troops at St. Petersburg. Petersburg in 1915, about horses the economy of a competing country etc. being infected in US ports for British and French armies.

In the Contemporary Age – extraordinary intelligence has CONCLUSIONS been invested in the development and modernization of all There is information that there are still laboratories and categories of weapons. Each country classified biological plants specializing in the research and manufacture of programs at the highest level of secrecy; there is little biological weapons. Most of the results of such research are evidence today about the details of the programs being not intended to be published; however, a number of

research guidelines that testify to the trends in the infectious diseases that are not circulating in the respective improvement of biological weapons and their means of use country. can be deduced from the data published by researchers from We believe that the threats posed by bioterrorism are real several research institutes (e.g. the study of some of the and that it is mandatory to be prepared at any time to most dangerous communicable diseases in humans and prevent, combat and liquidate the consequences of "bio- animals that currently have a very narrow spreading area). chem" attacks, respectively the management of the Another evidence of concern in the field of biological consequences. weapons is that the military personnel of some states are regularly exposed to prophylactic vaccines against some

References:

1. Mihail-Silviu Tudosie, Teodora Bianca Eremia, Ioana Alexandra 4. https://ro.wikipedia.org/wiki/R%C4%83zboi_biologic Gal, Iulia Madalina Staicu, Viorel Ordeanu - Conceptul de razboi 5. http://www.ccpb.ro/despre-bioterorism/scurt-istoric-al-armei- biologic si atacurile biologice reale, Comunicare Conferinţa Anuală a si-razboiului-biologic Spitalului Universitar de Urgenţă Militar Central “Dr. Carol Davila”

Bucuresti 10-13 octombrie 2018 6. „Convenţia privind interzicerea perfecţionării, producţiei şi stocării armelor bacteriologice (biologice) şi cu toxine şi la 2. Ordeanu V. et all. Microbiologie si protectie medicala contra distrugerea lor (BTWC)” http://www.ancex.ro/? pag=69 armelor biologice, Editura Universitara Carol Davila, Bucuresti, 2008 7. Convenţia pentru Arme Biologice, http://www.ccpb.ro/ despre- 3. https://en.wikipedia.org/wiki/CBRN_defense bioterorism/conventia-pentru-arme-biologice

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

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 trunk and the other one will issue the superior mesenteric artery. In the case where the first and the fourth root The celiac trunk and the superior mesenteric aorta are disappear, then the celiac-mesenteric trunk will originate. collateral branches of the abdominal aorta that are originating independently from its trunk, assuring the MATERIAL AND METHODS vascularization of the biggest part of the digestive tube and its annexed glands as well as the vascularization of the The material for this study comprised of 16 angiography- spleen. There have been cases where both arteries computed tomography (CT), performed with GE LightSpeed originated from the aorta through a common trunk, the VCT high image resolution 64-slice CT system and GE celiac-mesenteric trunk, with frequencies of [1] and 3% [2, 3] LightSpeed 16- slice CT system, both systems within the – most authors pointing a percentage between 1.0 and 2.5% of the cases. According to [4], during the embryonal 1 “Ovidius” University of Medicine and Pharmacy, Constanţa development, out of the 4 roots of the omphalomesenteric 2 ‘’Agripa Ionescu’’ Hospital, Bucharest 3 artery, roots 2 and 3 will disappear and the persistent root ‘’Carol Davila’’ University of Medicine and Pharmacy Bucharest 4 Arestetic Clinic Galati will unite by longitudinal anastomosis resulting into left 5 ’’Dunarea de Jos’’ University from Galati gastric artery. The persistent root will give birth to the celiac 6 General Hospital CFR Galati

premises of the Clinical Emergency County Hospital “Sf. all cases the aortic ostium had an oval shape. In 8 cases Andrei” in Constanta. The above-mentioned 12 cases were (66.67% of the cases) the long axis was horizontal and in 4 studied out of 2220 patients that presented for a specialist cases (33.33% of the cases), the axis was vertical. By consult for various medical reasons, during the period comparing the vertical diameter of the aorta, the ostium between July 2012 and June 2016, in Dobrogea area of the trunk had a vertical diameter with values ranging between country, south - eastern part of Romania. From the total 34.92 to 55.26% of the aortic one, whereas in the case of the number of patients, 830 were females (37.39%) and 1390 horizontal diameter it presented with values ranging were males (62.61%). The study was conducted with respect between 41.79 to 54.37% of the horizontal aortic diameter. to the following parameters: the level of origin of the celiac- At the level of its origin, the celiac-mesenteric trunk created mesenteric trunk from the aorta in relation to the vertebral and angle with the aortin wall, with values ranging between column, the trajectory and the angle formed from the origin 30○ to 90.2○ – extreme values had been found in one for each of the celiac-mesenteric trunk with the aortic wall, the value, most frequent value for the angle being of 60○. This exterior diameter as well as the endovascular diameter of explains the trajectory of the celiac-mesenteric trunk, most the celiac-mesenteric trunk at the level of its aortic origin, its frequently position being transverse anterolateral to the length up to its bifurcation, the angle formed between its right, an aspect met in 10 cases (83.33% of the cases) and two terminal branches as well as the diameter and the only 2 cases having a horizontal trajectory (transversal) trajectory. presenting with an angle of 90,2○ respectively 90,3○.

RESULTS The length of the celiac-mesenteric trunk had values ranging between 21.8 to 42.5 mm, most frequently met values In the present study, we met 12 cases with celiac-mesenteric ranging from 30.7 to 33.5 mm. 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 bifurcation of the celiac-mesenteric trunk into the two the trunk was located in the upper half of the L1 vertebra – arteries had an angle with values ranging from 82.2○ to intervertebral disk between L1 and L2 vertebrae. In 7 cases 120.7○, most frequently met values being over 90○ (83.33% (58.33% of the cases) the origin was located at the level of of the cases). In the case that, after the bifurcation, the the upper half of the L1 vertebra, most frequently near the superior mesenteric artery had a transverse anterolateral to upper margin of the vertebral body. In 3 cases (25% of the the right trajectory, the celiac trunk would always be cases), the celiac-mesenteric trunk originated in the lower ascending to the right, sometimes close to a vertical position. half of the L1 vertebra, whereas in 2 cases (16.67% of the The celiac trunk resulting from the celiac-mesenteric cases) it originated at the level of the intervertebral disk L1 bifurcation had an external diameter with values ranging – L2. from 6.2 to 10.2 mm, extreme values have been met in only The celiac- mesenteric trunks originating from the aorta was one case for each value; the rest of the cases with values located higher than the origin of the renal arteries, at a ranging between 8.0 to 9.2 mm. In relation to the external distance of 8.9 – 20 mm from the right renal artery, diameter of the celiac-mesenteric trunk from which it respectively 9.2 – 22.8 mm from the left renal artery. This originated, the celiac trunk had an external diameter with indicates that the right renal artery originates most smaller values by 0.7 to 4.2 mm, representing 65.57 – frequently from the aorta than the left renal artery. 92.47% of its external diameter.

The celiac-mesenteric trunk originating from the aorta had The length of the celiac trunk up to its ending ramification an external diameter with values ranging between 8.7 to had values ranging between 6.3 to 16.8 mm – extreme 13.4 mm, in 8 cases (66.67% of the cases) with a diameter measures were found in only one for each case. All cases ranging between 11.4 and 13.4 mm. By comparing the presented with a hepatosplenic trunk with the left gastric external diameter of the celiac-mesenteric trunk with the artery originating from the abdominal aorta in 10 cases external diameter of the abdominal aorta at the level of its (83.33% of the cases), at a distance of 15.1 – 18 mm above origin, we have discovered differences in values, ranging the origin of the celiac-mesenteric trunk. In one case, the left from 9.3 to 13.8 mm between the two diameters, gastric aorta originated from the terminal bifurcation of the representing 40.09 – 58.01% of the external aortic diameter. celiac trunk whereas in the other case it originated from the celiac-mesenteric trunk before its ending ramification. The aortic ostium of the celiac-mesenteric trunk had a vertical diameter with values ranging from 8.8 to 13.1 mm – The endovascular ostium of the celiac trunk had a vertical the horizontal diameter ranged between 8.4 to 11.2 mm. In diameter with values ranging from 7.1 to 8.6 mm, with a

32 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine horizontal diameter of 6.6 to 8.6 mm. In 11 cases (91.67% of By comparing the external diameters of the celiac trunk and the cases) the horizontal diameter was bigger than the the superior mesenteric aorta, we have discovered that in 11 vertical diameter by 0.5 – 1.3 mm, thus having an oval- cases, the superior mesenteric aorta had a smaller diameter shaped horizontal long axis. In only one case (8.33% of the than the celiac trunk, representing 47.83 – 83.33% of the cases) the diameter of the ostium was bigger vertically than diameter of the celiac trunk and only in one case the horizontally, with a difference of 0.5 mm thus having an oval diameter of the celiac trunk was smaller than the one of the shape with a vertical long axis. superior mesenteric artery, representing 83.73% of its diameter. The superior mesenteric artery resulted by the ramification of the celiac-mesenteric trunk had an external diameter with DISCUSSIONS 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 Analyzing the results, we had and comparing them to the of the celiac-mesenteric trunk. data in the existing literature referring to the morphological characteristics of the celiac-mesenteric trunk, we have Table: Percentage frequency of the celiac-mesenteric trunk discovered there is no thorough description of these, most Author CMT frequency Differences authors mentioning only the frequency as a vascular variation. Adachi 2.4 % - 1.86 % Babu 2.79 % - 2.25 % By comparing the results of the study with the data existing in the literature we had the possibility to consult, we Chen 0.7 % - 0.16 % discovered that our results were the same with the results Eaton 0.54 % 0 of [1], whereas in the rest of the cases we found differences Ferrari 1.7 % - 1.16 % with values ranging from 0.06 to 2.46%. Compared with the Jones 1.7 % - 1.16 % statistics of [5, 6, 7, 8, 9, 10] our results were smaller with values ranging between 0.06% [5] and 0.52% [10]. Compared Kornafel 1.5 % - 0.96 % with [11] the results we had were smaller by 0.96% and Lippert 3 % - 2.46 % values ranging from 1 to 2.25% we most frequently met Lipshutz 2.4 % - 1.86 % [Adachi, cited by 8, 12, 13, 14, 15, 16, 17, 18, 19]. Babu [19] Matusz 0.68 % - 0.14 % is the only author mentioning the frequency of the celiac- mesenteric trunk in both genders – our results on male cases Michels 2.5 % - 1.96 % being smaller by 0.46%. Unlike our study where the presence Mu CG 0.98 % - 0.44 % of the celiac-mesenteric trunk was met only in male cases, Natsume 0.60 % - 0.06 % Babu [19] discovers the presence of celiac-mesenteric trunk Nelson 2.0 % - 1.46 % having a wider spread within female cases (1.47% of the cases). In relation to the statistics of [2, 3], the results are Panagouli 0.76 % - 0.22 % lower, the difference being by 2.46%. Lippert [3] discovers Piquand 2.0 % - 1.46 % the presence of the gastro-hepato-spleno-mesenteric trunk Rio Branco 3.0 % - 2.46 % in 2% of the cases, a difference of 1.95% from our study, and Song 1.06 % - 0.52 % the hepato-spleno-mesenteric trunk with the origin of the left gastric aorta from the aorta in 1% of the cases, a Yadov 2.5 % - 1.96 % difference of 0.55% from our study. Babu [19] finds that in 3 Our study 0.54 % of the 0.86 % male cases (15.79% of the met celiac-mesenteric trunks), the total cases cases origin of the left gastric aorta was in the celiac trunk resulted from the celiac-mesenteric bifurcation at the level of the The endovascular ostium of the superior mesenteric artery abdominal aorta. In a case described by Anupama [20], from had a vertical diameter with values ranging from 6.8 to 8.5 the celiac trunk resulted the hepatic artery, the splenic mm, with a horizontal diameter of 6.2 to 8.5 mm. In 11 cases artery, the left gastric artery and a branch that participated (91.67% of the cases) the horizontal diameter was bigger in formation of the gastro-duodenal artery. In the specialist than the vertical diameter by 0.3 – 1.1 mm, having an oval literature, we have not met celiac-mesenteric trunk cases shape with a horizontal long axis. In only one case (8.33% of where the left gastric artery originated anteriorly to the the cases) the diameters of the ostium were equal, thus ending ramification of the celiac-mesenteric trunk, closer to having a round shape. its origin.

The length of the celiac-mesenteric trunk given by Anupama the fact that cases where the hepatic artery was the only one [20] is of 13.00 mm, Tugrul [21] specifics a length of 13.42 originating from the trunk weren’t taken into consideration mm, both values being smaller than the ones we found in as well as the methods used for the research. There is a our study by 8.80mm, respectively 8.38 mm smaller than the difference between the classical methods (dissections, minimum length and 29.5 mm, respectively 29.08 mm intramuscular injections) in relation to the modern methods, smaller than the length we have measured in our study. especially MDCD that has better results than the conventional angiography [17, 23]. With modern exploration With regards to the diameter of the celiac-mesenteric trunk, methods, it has been noted that a greater number of Tugrul [21] finds an external diameter of 13.98 mm, a vascular variants and malformations have been observed diameter bigger by 0.58 mm than what we have measured than those reported in the specialist literature involving for the maximum value and with 5.28mm bugger than the other methods. We could add as a cause to the differences minimum diameter. Compared to our results Tugrul [21] and the probable existence of some peculiarities related to finds the celiac trunk resulting from the celiac-mesenteric the geographical area, which exist between authors who bifurcation with a diameter (7.09 mm) bigger by 0.89 mm carried out their research on different meridians of the from the minimum diameter and smaller by 3.11 mm from world. the maximum value of the diameter we have measured. At the level of the superior mesenteric artery Tugrul [21] finds We consider the name of vascular malformation used by a diameter of 5.25 mm, bigger by 0.86 mm from the some authors when talking about the celiac trunk is not the minimum diameter and smaller by 3.25 mm than the values correct name, whereas vascular variant seems a more of the maximum diameter we have measured in the study. appropriate name since all vascular branches of the two Hemanth [22] finds an external diameter of 8.7 mm for the arteries are present, having the same morphological superior mesenteric artery, bigger by 4.3 mm than the characteristics as in the case where they originated minimum diameter, respectively by 0.2mm than the independently from the aorta, also because they don’t affect maximum value within our study. the vascular territories they serve.

The present study is interesting not only for a morphologist CONCLUSION but also, knowing the different types of anatomical variants There is a relatively low frequency of celiac-mesenteric trunk is fundamental for the planning of abdominal surgical cases described in the literature, our case having the lowest procedure and is important to the radiologist as well, as frequency. The differences between different authors is specified by [10, 23]. related to the number of cases they have studied and due to

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Article received on April 3, 2019 and accepted for publishing on June 3, 2019. 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 treatment for esophageal cancer in order to maintain local disease control and prolong life expectancy. The median Esophageal cancer is the seventh most common cause of survival is 15-18 months, and the 5-year survival rates are cancer-related deaths worldwide. In 2012, 455,800 people 20-25% after esophagectomy [2]. were diagnosed with, and 400,200 people died from esophageal cancer [1]. Failure in the treatment is generally due to recurrence and metastases. Developments in standard therapy are ongoing. Surgical resection has traditionally been the primary Radiotherapy can provide locoregional control in esophageal cancer, while chemotherapy has both local and systemic 1 Dışkapı Yıldırım Beyazıt Research and Education Hospital, antineoplastic effects. With the development of Ankara, Turkey multidisciplinary treatment approaches, the use of 2 Ankara Onkoloji Research and Education Hospital, Ankara, Turkey 3 Yıldırım Beyazıt University, Ankara, Turkey Corresponding author: Tülay Eren 4 Numune Research and Education Hospital, Ankara, Turkey [email protected]

36 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine chemoradiotherapy (CRT) in addition to surgery has become radiotherapy sequence in the treatment of esophageal the most frequently used treatment method [3]. cancer are still controversial. No standard guideline has been created in this particular. The main aim of this study was to In esophageal cancer treatment, the results obtained from evaluate the most effective local treatment modality in non- surgical treatment alone are not satisfactory in terms of metastatic, middle and lower esophageal squamous cell locoregional recurrence or distant metastasis rates. This has carcinoma (SCC) according to real-life data. paved the way for multimodal treatment approaches. Together with the multimodal treatment, METHODS chemoradiotherapy (CRT) added to surgery in the preoperative or postoperative period, aims to provide A total of 136 patients diagnosed between the years 2005- disease-free survival and an increase in life expectancy. 2016 in 3 different oncology clinics were included in the study. The patient data were reviewed retrospectively. Preoperative chemoradiotherapy has begun to be used to Patients aged 18-70 years, without distant metastasis, increase the R0 resection rates by reducing the tumor stage treated for curative purposes, with ECOG performance before surgery, thereby contributing to survival [4-10]. The status 0-2, with appropriate liver/renal reserve, middle and application of surgery after preoperative lower esophagus involvement, and with SCC histology were chemoradiotherapy is now a well understood and effective included in the study. Patients with adenocarcinoma treatment [11, 12]. In the ChemoRadiotherapy for histopathology, with cervical esophagus involvement, and Oesophageal cancer followed by Surgery Study (CROSS), a those who only received RT as a local treatment were not pilot study related to preoperative chemoradiotherapy, the included in the study. preoperative chemoradiotherapy was reported to increase the median OS approximately 2-fold when compared to All the patients were applied with thorax and entire surgical treatment alone (49.4 vs 24.0 months) [4]. abdomen computed tomography (CT) or positron emission tomography (PET-CT) or endoscopic ultrasonography (EUS) In the literature, there are data about the postoperative examinations for the purpose of staging prior to local (adjuvant) activity of chemo-radiotherapy in addition to its treatment. The patients were divided into 2 groups as local preoperative activity. In the past, the major problem in and local advanced disease according to the radiological applying chemoradiotherapy in the postoperative period results at the time of diagnosis. Radiologically, patients with was the inability of patients to complete the scheduled T4 tumors or lymph node positivity were considered to have treatment due to poor performance of the patients after locally advanced disease, while non-T4 patients with lymph surgery, but currently developing surgical and radiotherapy node-negativity were considered to have local disease. techniques have partly removed this problem. Studies by Rice et al. [13] and Bedard et al. [14] have demonstrated the The patients were divided into 3 groups as those who survival advantage of postoperative CRT. In the underwent only surgical resection, only definitive CRT retrospective study by Rice, the median survival was stated (dCRT), and multimodal treatment (preoperative CRT or to be 28 months with surgical postoperative CRT, and 15 postoperative CRT) according to the curative local treat- months with surgery alone (p<0.05). In the study by Bedard, ments they received and were evaluated comparatively. the median overall survival was reported to be 47.5 months Platinum-based combination therapies (fluorouracil or with postoperative CRT and 14.1 months with surgery alone taxane) were administered concomitantly with the chemo- (p=0.001) [14]. therapy regimen in patients receiving chemoradiotherapy.

Following the studies showing the benefits of preoperative In CRT planning, a 3 mm interslice distance CT scan was and postoperative chemoradiotherapy, studies about performed on all patients in the supine position. In patients treatment sequence emerged. Current data on the undergoing definitive and preoperative chemoradiotherapy, prognostic effect of local treatment sequence in esophageal the gross tumor volume (GTV) was determined for primary cancer remain controversial [15, 16]. In a study based on the mass and involved lymph nodes using thoraco-abdominal SEER data, it was determined that preoperative CRT ensured CT, PET-CT, endoscopy and EUS information, if available. The better survival compared to postoperative CRT [15], while a clinical target volume (CTV) was established by giving a prospective study reported no difference in survival margin of 4 cm in the superior-inferior direction and 1 cm in between taking the CRT in the preoperative or postoperative the radial direction to the primary mass. The planning period [16]. volume was obtained by allowing 1 cm extra margin to this. The spinal cord, lungs, and organs at risk, such as the heart, In the light of this information, the prognostic implications remaining within the area were contoured. In postoperative of optimal multimodal treatment, surgery and chemo-

therapy, bilateral supraclavicular or celiac lymph nodes were continuous numerical variables, and as number (n) and included in the area in the location of all mediastinum and percentage (%) for categorical variables. primary masses. The progression and overall survival rates of all cases were The gastroesophageal intersection and proximal stomach investigated using Kaplan-Meier survival analysis. The 2-year were included in the area in distal localized tumors. and 3-year cumulative progression and overall survival rates together with mean lifespan and 95% confidence intervals The radiotherapy (RT) plans were made by applying the 3- for these terms were calculated. The demographic dimensional conformal technique. Patients undergoing characteristics of the patients were assessed using definitive CRT (dCRT) received a total of 50.4 Gy descriptive statistical methods. Parameters that were radiotherapy, and those undergoing pre-operative or significant in univariate analysis were assessed using Cox postoperative CRT received a total of 45 Gy radiotherapy, regression multivariate analysis. A value of p<0.05 was which was applied as 1.8 Gy daily for 5 days a week. accepted as statistically significant. All patient records were reviewed clinically, pathologically and in terms of treatment characteristics. The long-term RESULTS survival data of patients were obtained from the patient files A total of 136 patients were evaluated comprising 32.4% and from the data of the Turkish civil registry office. (n=44) in the surgical group, 36% (n=49) in the definitive CRT Approval for the study was granted by the Ethics committee (dCRT) group, and 31.6% (n=43) in the multimodal treatment of Sağlık Bilimleri University Dışkapı Yıldırım Beyazıt Training group. Of the total patients, 52.2% were female and 47.8% and Research Hospital. were male.

The data were analyzed using SPSS 18.0 for Windows The demographic characteristics of the patients are shown software. Descriptive statistics were expressed as mean ± in Table 1. standard deviation or median (minimum-maximum) for non-

Table 1: Demographic characteristics of the patients Multimodal Surgery dCRT Treatment p Value (n=44) (n=49) (n=43) Age (years) Median (min-max) 52 (32-76) 58 (25-77) 50 (32-70) 0.001 Female 26 (59.1%) 21 (42.9%) 24 (55.8%) Gender 0.249 Male 18 (40.9%) 28 (57.1%) 19 (44.2%) Smokers 20 (45.5%) 26 (53.1%) 12 (39.5%) Smoking 0.426 Non-smokers 24 (54.5%) 23 (46.9%) 26 (60.5%) Users 15 (34.1%) 14 (28.6%) 19 (44.2%) Alcohol Use 0.288 Non-users 29 (65.9%) 35 (71.4%) 24 (55.8%) Present 15 (34.1%) 16 (32.7%) 8 (18.6%) Comorbid disease 0.208 Absent 29 (65.9%) 33 (67.3%) 35 (81.4%)

Cancer history in Present 9 (20.5%) 14 (28.6%) 9 (20.9%) 0.581 family Absent 35 (79.5%) 35 (71.4%) 34 (79.1%) Well 2 (4.5%) 5 (10.2%) 4 (9.3%) Tumor Grade Moderate 8 (18.2%) 6 (12.2%) 5 (11.6%) 0.240 Poor 3 (6.8%) 12 (24.5%) 4 (9.3%)

Location of Mid-esophagus 18 (40.9%) 25 (51.0%) 25 (58.1%) 0.271 tumor Lower esophagus 26 (59.1%) 24 (49%) 18 (41.9%) Early 26 (59.1%) 11 (22.4%) 20 (46.5%) Pre-clinical stage 0.001 Locally advanced 18 (40.9%) 38 (77.6%) 23 (53.5%)

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

When the postoperative stages of 44 patients treated with determined in 64% (n=16) preoperative CRT group. In this surgery alone were evaluated, it was seen that 15.9% (n=7) group, 4 patients died in the postoperative period due to of these patients were stage 1, 40.9% (n=18) were stage 2, complication. In postoperative CRT group, 11.1% (n=2) of the and 43.2% (n=19) were stage 3. Adjuvant chemotherapy patients were stage 1, 16.7% (n=3) were stage 2, and 72.2% with cisplatin/fluorouracil combination was administered to (n=13) were stage 3 after surgery. 27.3% (n=12) of the patients in this group. The median follow-up time was 31 months (2-142) in the One patient died in the intensive care unit due to surgical surgical group, 11 months (2-106) in the definitive CRT complications in the postoperative period. group, and 20 months (4-140) in the multimodal treatment group. In the group of patients receiving definitive CRT, 1 patient died due to complications during treatment. The median disease-free survival was 21 months (95% CI 14- 27) in the surgical group, 8 months (95% CI 4-11) in the The number of patients receiving preoperative CRT was 25 definitive CRT group and 18 months (95% CI 0-39) in the and the number of patients receiving postoperative CRT was multimodal treatment group (p=0.059). DFS curve shown in 18 in the multimodal treatment group. In the multimodal Figure 1. treatment group, a pathological complete response was

Figure 1: Disease Free Survival

The 2-year disease-free survival (DFS) was 43% in the surgical In the multimodal treatment group, the median OS was group, 33% in the definitive CRT group, and 47% in the found to be 47 months (95% CI 0-99) in the preoperative CRT multimodal treatment group (p=0.05). group, and 64 months (NA) in the postoperative CRT group. The difference between the groups was not statistically The median overall survival (OS) was 40 months (95% CI 0- significant (p=0.302). OS curve when the multimodal group 92) in the surgical group, 19 months (95% CI 15-22) in the was divided into two as preoperative and postoperative CRT definitive CRT group and 54 months (95% CI 11-96) in the shown in Figure 3. multimodal treatment group. The difference between the groups was statistically significant (p=0.012). Cumulative OS DISCUSSION curve shown in Figure 2. Surgical resection is the basic method that is conventionally The 2-year OS was 68% in the surgical group, 40% in the effective in providing local disease control in non-metastatic definitive CRT group and 59% in the multimodal treatment esophageal cancer treatment. However, due to high group (p=0.01). locoregional recurrence and distant metastasis rates, surgical resection alone is insufficient. The median overall

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 In the present study, the disease-free survival was 21 5-year survival rates after esophagectomy were reported months and the overall survival was 40 months in the group 23% [17]. In another study in which the surgery was of patients who underwent surgery alone. In the surgical compared with surgery after preoperative CRT, and patients group, 27.3% of the patients (n=12) received adjuvant were evaluated in the early stage, the median OS was chemotherapy with Cisplatin/Fluorouracil combination. reported as 18.6 months in the patients who underwent Compared to general literature data, the patients included surgery [9]. in the current study had longer DFS and OS. Possible reasons

40 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine for this may be the exclusion of upper esophageal tumors, underwent postoperative CRT after esophagectomy, and which are known to have a worse prognosis, and the fact 28.1% in patients who underwent surgery alone [20]. that approximately 25% of the patients who underwent Following studies showing the contribution of preoperative surgery were administered adjuvant chemotherapy. and postoperative CRT in esophageal cancer, questions were Although surgical resection is still the basic standard asked about the prognostic contribution of surgery and the approach in non-metastatic esophageal tumors, definitive sequence of chemoradiotherapy and what should be the chemoradiotherapy is still an effective local treatment optimal treatment sequence. In a prospective study by Lv et alternative for patients not suitable for curative surgery [18]. al., where preoperative CRT, postoperative CRT, and surgery In one of the largest studies in which a direct comparison were compared, both 5-year OS (43.5% vs 42.3%) and 5-year was made between definitive chemoradiotherapy and DFS (37.5% vs 37.2%) were found to be similar between the surgery, the two-year survival rates were 45.4% in the preoperative CRT and postoperative CRT groups (p>0.05) definitive CRT group and 56.2% in the surgical group [19]. [16]. Chen et al. emphasized that CRT together with surgery This study supports the idea that all patients who cannot extended the overall survival independently of the undergo surgery due to high risk may be recommended treatment sequence [24]. definitive chemoradiotherapy independent of the histology. In a retrospective study in which Hsu et al. evaluated the In the present study, the definitive CRT group showed a optimal treatment sequence for locally advanced disease-free survival of 8 months, an overall survival of 19 esophageal cancer in 2017, the preoperative CRT and months, and a 2-year survival rate of 43%. These results are postoperative CRT groups were found to have similar consistent with the literature. median OS (26 vs 23 months, p=0.31) [25]. A statistically insignificant but clinically significant difference was found in Although surgical resection is the curative treatment disease-free survival (16.7 months vs 10.4 months, p=0.061). approach for esophageal cancer, the poor long-term survival However, in that study, the rate of stage 3 patients was outcomes have encouraged multimodal treatment higher in the group receiving postoperative CRT. approaches in this patient group. With preoperative chemoradiotherapy as one of the multimodal treatment Based on this information, in the present study, the methods, the treatment of micro metastases and regression multimodal treatment group was found to be superior to of the tumor stage contribute positively to the overall patients who underwent surgery only or definitive CRT in survival rates of patients by increasing the rate of curative terms of both overall survival and disease-free survival. The resection [4-10]. treatment sequence in the multimodal group was not found to affect the overall survival and disease-free survival and In the CALGB 9781 study, the median survival was 4.4 years these results are consistent with the current literature. vs. 1.7 years (p=0.002) and 5-year survival rates were reported to be 39% vs 16% in favor of multimodal treatment Since the present study was retrospective, it has some in esophagectomy after preoperative CRT, where the limitations. As patients from three different oncology clinics cisplatin/fluorouracil combination was used compared with were included, it was not possible to obtain information on esophagectomy only [10]. In the CROSS trial, patients who which criteria the patients were directed to different underwent surgery after preoperative chemoradiotherapy treatment groups when the initial treatment plan was made. and patients who underwent surgery only were compared. No information could be obtained about why the patients The concomitant paclitaxel-carboplatin combination was with local disease could not be operated on. The fact that used in this study. It was reported that the preoperative CRT patients undergoing surgery were operated on by different improved the survival times compared to the surgery group surgical clinics was another limitation. Not all toxicity data (OS 49.4 months vs 24.0 months, HR for survival, 0.657; 95% could be obtained due to the retrospective nature of the CI, 0.495-0.871; p=0.003) [4]. The long-term results of the study. CROSS trial also showed that the contribution to overall In conclusion, it was determined that the multimodal survival continued [12]. treatment of squamous cell medium and lower esophageal Another multimodal treatment approach is postoperative tumors increased the disease-free survival and overall adjuvant CRT. Many studies have shown the contribution to survival, but the treatment sequence had no effect in this survival of postoperative chemoradiotherapy in patients particular. However, there are questions that still need to be who have undergone esophagectomy [13, 14, 20, 21, 22, 23]. answered for operable esophageal tumors, such as what the In a study by Hwang et al., the 3-year OS rates in squamous ideal local treatment modalities and combinations are, cell esophageal cancer were 44.9% in patients who whether it is preferable to apply the chemotherapy scheme

synchronously with CRT, and the location of postoperative randomized phase studies on these subjects. adjuvant chemotherapy. There is a need for further

References:

1. Torre La, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. R. The Role of Surgery And Postoperative Chemoradiation therapy Global Cancer Statistics, 2012. CA Cancer J Clin. 2015; 65: 87-108. in Patients with Lymph Node Positive Esophageal Carcinoma. 2. Posner Mc, Minsky Bd, Ilson Dh. Cancer of the Esophagus. In: Cancer. 2001;91: 2423–2430 Devita Vt, Lawrence Ts, Rosenberg Sa, Editors. Devita, Hellman, And 15. Hong JC, Murphy JD, Wang SJ, Koong AC, Chang DT. Rosenberg’s Cancer: Principles & Practice of Oncology. 10th Ed. Chemoradiotherapy Before And after Surgery for Locally Advanced Philadelphia: Wolters Kluwer, 2015: 574-612 Esophageal Cancer: A Seermedicare Analysis. Ann Surg Oncol. 3. Lv J, Cao XF, Zhu B, Ji L, Tao L, Wang DD. Effect of Neoadjuvant 2013;20:3999-4007. Chemoradiotherapy On Prognosis And Surgery for Esophageal 16. Lv J, Cao XF, Zhu B, Ji L, Tao L, Wang DD. Long-Term Efficacy of Carcinoma. World J Gastroenterol. 2009; 15: 4962-4968. Perioperative Chemoradiotherapy On Esophageal Squamous Cell 4. Van Hagen P, Hulshof MC, Van Lanschot JJ et al. Preoperative Carcinoma. World J Gastroenterol. 2010;16:1649-54 Chemoradiotherapy for Esophageal or Junctional Cancer. N Engl J 17. Orringe MB, Marshall B, Iannettoni MD. Transhiatal Med. 2012;366: 2074–2084. Esophagectomy: Clinical Experience and Refinements. Annals of 5. Urba SG, Orringer MB, Turrisi A, Lannettoni M, Forastiere A, Surgery. 1999; 230: 392–403 Strawderman M. Randomized Trial of Preoperative Chemoradiation 18. Minsky BD, Pajak TF, Ginsberg RJ et al. Int 0123 (Radiation versus Surgery Alone in Patients with Locoregional Esophageal therapy Oncology Group 94-05) Phase III Trial of Combined-Modality Carcinoma. J Clin Oncol. 2001;19: 305–313 therapy for Esophageal Cancer: High-Dose versus Standard-Dose 6. Burmeister BH, Smithers BM, Gebski V, et al. Surgery Alone versus Radiation therapy. J Clin Oncol 2002; 20: 1167–74. Chemoradiotherapy Followed by Surgery for Resectable Cancer of 19. Reid TD, Davies IL, Mason J, Roberts SA, Crosby TD, Lewis WG. the Esophagus: A Randomized Controlled Phase III Trial. Lancet Stage for Stage Comparison of Recurrence Patterns after Definitive Oncol. 2005; 6: 659–668. Chemo-Radiotherapy or Surgery for Esophageal Carcinoma. Clin 7. Lee JL, Park SI, Kim SB, et al. A Single institutional Phase III Trial of Oncol 2012; 24: 617–24. Preoperative Chemotherapy with Hyperfractionation Radiotherapy 20. Hwang JY, Chen HS, Hsu PK, et al. A Propensity-Matched plus Surgery versus Surgery Alone for Resectable Esophageal Analysis Comparing Survival after Esophagectomy Followed by Squamous Cell Carcinoma. Ann Oncol. 200415: 947–954. Adjuvant Chemoradiation to Surgery Alone for Esophageal 8. Mariette C, Dahan L, Mornex F, et al. Surgery Alone versus Squamous Cell Carcinoma. Ann Surg. 2016;264:100-6. Chemoradiotherapy Followed by Surgery for Stage I And II 21. Hsu PK, Huang CS, Wang BY, Wu YC, Hsu WH. Survival Benefits Esophageal Cancer: Final Analysis of Randomized Controlled Pphase of Postoperative Chemoradiation in Lymph Node-Positive III Trial FFCD9901. J Clin Oncol. 2014; 32: 2416–2422 Esophageal Squamous Cell Carcinoma. Ann Thorac Surg. 9. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy 2014;97:1734-41. Followed by Surgery Compared with Surgery Alone in Squamous Cell 22. Chen J, Pan J, Liu J, et al. Postoperative Radiation therapy with Cancer of the Esophagus. N Engl J Med. 1997; 337:161–167. or without Concurrent Chemotherapy for Node-Positive Thoracic 10. Tepper J, Krasna MJ, Niedzwiecki D, et al. Phase III Trial of Esophageal Squamous Cell Carcinoma. Int J Radiat Oncol Biol Phys. Trimodalityity therapy with Cisplatin, Fluorouracil, Radiotherapy, 2013;86:671-7. And Surgery Compared with Surgery Alone for Esophageal Cancer: 23. Wang ZW, Luan ZP, Zhang W, et al. Postoperative CALGB 9781. J Clin Oncol. 2008;26: 1086–1092. Chemoradiotherapy İmproves Survival in Esophageal Squamous Cell 11. Jang R, Darling G, Wong RK. Multimodality Approaches for the Cancer with Extracapsular Lymph Node Extension. Neoplasma. Curative Treatment of Esophageal Cancer. J Natl Compr Canc Netw. 2014;61:732-8. 2015;13:229-38. 24. Chen HS, Wu SC, Hsu PK, Huang CS, Liu CC, Wu Yc. The 12. Shapiro J, Van Lanschot JJ, Hulshof MC, et al. Neoadjuvant Prognostic Impact of Preoperative and Postoperative Chemoradiotherapy Plus Surgery versus Surgery Alone for Chemoradiation in Clinical Stage II and III Esophageal Squamous Cell Esophageal or Junctional Cancer (Cross): Longterm Results of A Carcinomas: A Population Based Study in Taiwan. Medicine Randomised Controlled Trial. Lancet Oncol. 2015;16:1090-8. (Baltimore). 2015 Jun; 94(25): e1002. 13. Rice TW, Adelstein DJ, Chidel MA, Et Al. Benefit of Postoperative 25. Hsu PK, Chen HS, Liu CC et al. Pre-versus Postoperative Adjuvant Chemoradiotherapy in Locoregionally Advanced Chemoradiotherapy for Locally Advanced Esophageal Squamous Esophageal Carcinoma. J Thorac Cardiovasc Surg. 2003;126:1590– Cellcarcinoma. J Thorac Cardiovasc Surg. 2017 Aug;154 (2):732-740. 1596. 14. Bedard EL, Inculet RI, Malthaner RA,Brecevic E, Vincent M, Dar

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Article received on April 10, 2019 and accepted for publishing on June 23, 2019. 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 and meta-analyses, published in English, were cited in this review. Diagnosis of stable coronary artery disease is vital for prognosis, classification and early treatment. Failure in doing RESULTS AND DISCUSSION so, might determine secondary events such as: disease progress, myocardial infarction or even death. Diagnosis and management

Current guidelines show that patients with stable angina According to current guidelines, patients with suspected who are suspected of CAD need to undergo a certain SCAD will follow a step-by-step approach for confirmation. protocol for classification and further analysis. After the clinical examination and basic tests applied (ECG, This review’s aim is to present the most used non-invasive bio-chemistry indicators, resting echocardiography), if the techniques for identification of CAD and to underline the cause of chest pain is none other than CAD and the left current development of imaging technology and the possible ventricle ejection fraction is higher than 50%, the evaluation reduction of invasive measures due to non-invasive of suspected SCAD commences (patients with LVEF<50% techniques. have a high risk for cardiovascular events and they should have ICA without further testing). [1] METHODS First step is to determine the pre-test probability of SCAD A PubMed review was performed, analyzing all publications from 1968 to 2019 concerning the topic “stable coronary artery disease” (keywords: coronary artery disease, PTP, 1 Clinical Emergency Hospital Bucharest, Romania stress echocardiography, SPECT, CMR, CCT). Human studies 2 Prof. Dr. Th. Burghele” Hospital, Bucharest, Romania

(PTP). This indicator is evaluated by the age, gender and the showed that for men a positive exercise test results in a 89% nature of symptoms for the suspected patient, and evaluates probability of CAD, and for women results in a 69% the probability of having a coronary artery disease before probability of CAD. Whereas, a negative exercise test leads realizing any tests. for men to a 37% probability of CAD and for women to an 18%. These values show that a large share of patients may Non-invasive imaging techniques that assess coronary artery be undetected after performing an exercise stress test. [8] disease usually have sensitivities and specificities around the value of 85% (coronary computed tomography angiography This method is useful only for patients that don’t have ECG – coronary CTA has the highest sensitivity (95%) [2] while abnormalities at baseline. For example, patients with Wolff- stress echocardiography has the highest specificity (94.6%) Parkinson-White syndrome, paced ventricular rhythm, LBBB, [3]). This is why for 15% of the patients, most imaging use of digitalis, atrial fibrillation, left ventricular hypertrophy techniques will be false positive and therefore, for these with repolarization changes or digoxin use, have a higher patients (with PTP < 15%) performing no non-invasive likelihood that the observed ST-segment depressions would imaging tests will bring less incorrect results. Therefore: happen because of the baseline pathology and not the CAD.  patients with PTP < 15% will not do any further Therefore, in these patients the ECG results aren’t investigations; interpretable and exercise ECG testing should not be  patients with PTP between 15-65% are recommended to performed. [9] have an exercise ECG as the initial test and afterwards if Despite all the results, for low-risk patients, for example necessary, perform imaging tests; women, the standard ECG exercise treadmill test should be  patients with PTP between 66-85% must have a non- the first diagnostic strategy, because of its availability and invasive imaging test for confirmation; lower costs of usage. Additional imaging techniques, like  patients with PTP over 85% are assumed to have SCAD, so myocardial perfusion imaging (MPI) does not add any they don’t need further investigations. [1] substantial benefit to the exercise treadmill test, but As such, patients with PTP between 15%-85% are required increases diagnostic costs significantly [10]. to be assessed with non-invasive techniques for risk Also, it is safe to say that during exercise testing, the risk of stratification and selection for invasive measures having myocardial infarction because of the increase in the (revascularization or ICA). [4] pro-coagulant activity, doesn’t increase for patients with Electrocardiogram exercise testing CAD (objectified angiographically) in comparison to those who don’t have CAD, meaning that the method is in general As described above, for patients with PTP within 15-65% for safe. [11] suspected SCAD, an exercise electrocardiogram will be the first and best option. Although this method is accessible for diagnosis of CAD, in the near future it will probably be replaced with other more According to the Bruce protocol, this test involves using a accessible, non-invasive imaging techniques. Cardio- treadmill or an exercise bicycle in which patients are goniometry (3D-ECG) was demonstrated to have a higher monitored using a continuous 12-lead ECG and their blood performance in diagnosis (sensitivity 75% vs sensitivity pressure measured, when they are exercising. The level of 68.1% - exercise ECG and specificity 74.4% vs specificity difficulty increases incrementally every 3-minutes until a 38.1% - exercise ECG) of CAD in women, and being able to certain target is reached (the predicted heart rate for the age have this efficacy without having to undergo stress-testing of the patient) or the patient cannot continue the test. [5] and being practically free-of-risk, surely proves an If ST-depression is present with a value of ≥ 0.1mV or 1 mm, improvement in easiness and performance in the diagnosis in one or more ECG leads, which persist at least 0.06-0.08 of CAD for the near future. [12] seconds after the J-point, the test detects a possible CAD. [1] Stress echocardiography Data shows that the usefulness of the test might come for its Another imaging technique for the assessment of stable CAD higher specificity, one study shows a sensitivity of 45%, and is stress echocardiography. This method usually involves a specificity of 85% [6] while another study shows higher mechanical stressor (exercise performed on a treadmill or a values for men (sensitivity – 40%, specificity – 96%) than for bicycle) or a pharmacological agent. women (sensitivity – 33%, specificity – 89%). [7] The principle of stress echocardiography is the identification Also, in a meta-analysis which compared the efficacy of of functionality for all cardiac walls and further classification exercise stress testing between 34 studies, results also into normal, ischaemic, viable or necrotic myocardium:

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- normal myocardium responds with normokinetic function systolic strain-rates and strains during ejection time during at rest and during stress it may have a normokinetic or dobutamine stress than nonischemic segments [18] and hyperkinetic function; Gupta et al., recently showed in a meta-analysis similar - ischaemic myocardium may have a normal function at rest, results, analysis of longitudinal strain imaging having higher but during stress its response worsens, having a AUC-ROC prediction of CAD (0.92) than assessment of wall hypokinetic/akinetic/dyskinetic function; motion (0.83). [19] - viable myocardium testing in dysfunctional myocardium at The newest advancement in echocardiography for detecting rest shows a improvement during stress response because it CAD markers is the 3D-speckle tracking echocardiography would indicate a region of hibernating myocardium that (3D-STE). One of the most used scoring systems to objectify improves its function after revascularization; CAD severity is the Gensini score. In one study, using 3D-STE - necrotic myocardium doesn’t improve its function during to measure 4 parameters of CAD (global longitudinal strain – stress, a region of dysfunctional myocardium at rest has its GLS, global circumferential strain – GCS, global radial strain function fixed. [13] – GRS and global area strain – GAS) it had been found that Stress echocardiography using exercise stress is preferable patients found with critical CAD after coronary angiography because it provides additional data like exercise time, had significantly worse values of GLS,GCS,GRS,GAS than workload, heart rate and blood pressure variability. patients with noncritical CAD. Also the Gensini score had a Pharmacological stress using dobutamine can be used for significant positive linear correlation with GLS and GAD, patients who are unable to exercise. [1] meaning that 3D-STE was a very good method do identify the grade of severity of CAD. [20] Also using dobutamine bring the advantage of assessment of viability more accurately than exercise stress SPECT (Single photon emission computed tomography) – echocardiography. Ischaemic but viable myocardium at low Myocardial perfusion scintigraphy doses of dobutamine (10-20 μg/kg/min) improves its One of the most used imaging techniques, uses similar function, but at high doses (40 μg/kg/min) its function principles like the previously described methods. It uses worsens. This effect is due to the initial inotropic function of either exercise stress or pharmacological stress (e.g. dobutamine at low doses, whereas in high doses its function adenosine, dipyridamole, dobutamine, regadenoson) and changes to chronotropic and especially vasodilatory. [14] measures the level of uptake of radioactive tracers at rest Using additional contrast to the method (by using level and stress level from the myocardium. In ischemic microbubbles of encapsulated gas) can bring enhancement tissue, due to the lower blood flow in stress response, the of the images viewed, by improving image quality, accuracy uptake of the tracer is reduced, meaning a positive test for of detection of CAD and reader confidence, especially when diagnosis of CAD. [4] certain segments cannot be visualized at rest. [15]. Newer Standard radiotracers are Technetium-99m (99mTc) or data show data coronary microvascular dysfunction (a Thallium 201 (201Tl), although the latter has a higher potential cause for chest pain) can be observed using radiation dose. New developments in this technology myocardial contrast echocardiography, a marker for possible (cadmium-zinc-telluride – CZT) show a significantly higher CAD, patients with this issue having lower hyperemic performance than conventional SPECT and a lower dose of perfusion and microvascular flux rate than patients with radiation. [21] Also another radiotracer (for PET) that is normal microvascular function. [16] frequently used is Rubidium 82 (82Rb) that is associated with Diagnosis of CAD using stress echocardiography is quite lower radiation exposure and high sensitivity (82%) and efficient. Exercise stress echo, dobutamine and dipyridamole specificity (90%) for detecting ischaemia. [22] stress echo show sensitivities of 85%/80%/78% and The method also compares ischaemic areas of myocardium specificities of 77%/86%/91% for detection of CAD, which to normal areas. Some patients (with triple vessel disease) are significantly better than electrocardiogram exercise whom hearts have a widespread ischemia, will be detected testing, and similar to SPECT [17] false-negative for CAD because of the lack of inducing Also, using strain-rate imaging and tissue Dopple imaging ischemia in the underperfused myocardium, proving a can improve the quality of detection for CAD. Because the limitation of the method. [23] interpretation of images in most echocardiographies are Another limitation of the method would be diagnosis of CAD subjective and prone to errors, measuring strain-rate can in patients with left bundle branch block (LBBB). In those determine an objective view on the diagnosis. Voigt et al patients, the intraventricular septum has a delay in showed that ischemic segments had significantly higher peak

contraction (being dyskinetic), and in the moment of image blood flow is excellent and superior to the relative acquisition may have a lower thickness, indicating a LAD measurement of tracer uptake, being more efficient for the territory ischaemia, and thus a false-positive result. [24] detection of CAD and eliminating false-negative patients with balanced ischaemia (triple vessel disease). [31] Also, for asthmatic patients that are undergoing SPECT, using adenosine is a contraindication because of the possible New technology in PET-MPI for diagnosis of CAD show precipitation of bronchospasm due to activation of all similar results as described above, for usage of flurpiridaz 18F adenosine receptors (especially A1, A2B and A3). in comparison to SPECT, bringing more advantages for PET-

Regadenoson, a selective A2A agonist (for producing MPI (higher quality images, diagnostic certainty of hyperaemia) is currently used for these patients, because of interpretation, and sensibility of detection of CAD). [32] its sufficient hyperaemic response, less side effects, and Cardiac magnetic resonance comparable efficacy to adenosine. [25] One of the most advantageous methods of imaging The REASSESS study, in which in a prospective manner was techniques, because of the high-detail images, non- assessed the diagnostic performance of coronary computed invasivity and lack of any ionizing radiation, cardiac magnetic tomography angiography (CTA) vs. SPECT, showed that resonance can identify CAD, even better than the previous although many cases of stable CAD wouldn’t have been methods discussed. Similar to all CAD detection methods, is diagnosed by SPECT if invasive measures (angiography) uses a stress agent, exercise or pharmacological. wouldn’t have been taken, the overall performance of both of the methods (CTA and SPECT) was similar, in objectifying Stress cardiac magnetic resonance using both a bicycle [33] hemodynamically significant stenosis, having a similar and a treadmill [34] seems feasible for detection of CAD. accuracy (70% - CTA vs. 68% SPECT). [26] Recently, the EXACT study, which used stress CMR with a treadmill, showed a sensitivity of 79% and a specificity of The issue of false-negative results in SPECT, although 99% for detection of CAD after using a SPECT, also showed present, is indicated to have a low prevalence and thus, a higher agreement of diagnosis with angiography (k=0.82) low impact. For example, in 133 patients with normal SPECT than SPECT (k=0.46), demonstrating as such excellent results, only 16% had anatomically and functionally diagnostic value. [35] significant stenoses, and from 180 vessels analyzed with normal SPECT results, only 8.33% had stenoses. As such, the Pharmacological stress uses a vasodilator (adenosine or prevalence of false-negative cases in normal SPECT remains regadenoson) or dobutamine. Added in the vasodilator low and a normal result stays important in diagnosis and method is the administration of i.v. gadolinium contrast, to follow-up. [27] enhance the perfusion defects that can be seen in ischaemic walls. Using dobutamine requires a similar method like in SPECT also predicts efficiently long-term outcomes. Patients stress echocardiography, by viewing wall motion with ischaemia burden, who had SPECT and also underwent abnormalities in ischaemia response. [36] early coronary revascularization had significantly lower all- cause mortality and cardiac mortality in comparison to In CMR the assessment of CAD can be either qualitative (by patients who received only pharmacological therapy, visual assessment of presence and degree of ischaemia) or indicating a significant diagnostic value for the severity of quantitative by measuring absolute blood flow. A recent CAD by using SPECT. [28] study showed that quantitative analysis had similar diagnostic accuracy (83%) as qualitative (80%) and observers Usage of myocardial perfusion scintigraphy combined with considered a better approach to diagnose CAD using positron emission tomography is more accurate in quantitative CMR. [37] comparison to SPECT, having higher sensitivities (90% - PET, 85% - SPECT) and higher specificities (88% - PET, 85% - Recent data showed that CMR stress with perfusion in SPECT), also AUC-ROC prediction was higher for PET (0.95) in comparison with SPECT and PET showed good diagnostic comparison to SPECT (0.90), according to Mc Ardle et al. [29] accuracies, having a sensitivity of 89% (in comparison to SPECT – 88%, and PET – 84%) and a specificity of 76% (in A similar study showed better image quality and diagnostic comparison to SPECT – 61% and PET – 81%). Authors also accuracy of CAD for PET in comparison to SPECT (showing a considered that CMR could be a good alternative to PET, percentage of 78%/79% excellent image quality of having a similar diagnostic accuracy. [38] rest/stress PET scans vs. 62%/62% excellent image quality of rest/stress SPECT scans). [30] Nevertheless, current data shows that perfusion CMR has a better diagnostic performance value than SPECT, as shown Data also shows that using PET-MPI to determine myocardial

46 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine in the MR-IMPACT trial [39]. Also, the CE-MARC study Calcium scoring uses the principle of identifying coronary showed that CMR had better sensitivities than SPECT (88.7% calcification, without use of contrast. Any pixel above 130 for men vs. 50.9% for men – SPECT and 85.6% for women vs. Hounsfield units is defined as coronary calcification and can 70.8% for women – SPECT) and similar specificities, and be quantified using the Agatston score, which is dependent better diagnostic accuracies. [40] by the size of the plaque and the radiographic density. [46]

The CE-MARC 2 study compared the efficacy of CMR, NICE However, there can be identified obstructive coronary guidelines and SPECT in reducing the percentage of lesions which may be not calcified and vice-versa, critically unnecessary angiographies in patients with suspected calcified coronary arteries which aren’t yet obstructed. angina. The results showed that the CMR strategy Because of this matter, the preferable way to diagnose CAD determined a lower probability of unnecessary is CTCA. angiographies within 12 months than the NICE guidelines The North American Society for Cardiovascular Imaging strategy, CMR and SPECT reducing significantly the number (NASCI) agreed in their guidelines that patient selection is of angiographies in comparison to NICE guidelines. [41] needed before usage of CTCA. As such: The adverse effects for gadolinium-based contrast agents - because of contrast usage, any patients with known used in CMR have a low frequency (0.36%), the severe are history of severe anaphylactic reactions to contrast, have even less (0.033%), and these adverse effects are more contraindication to this method; physiological than allergic (most frequently were dyspnea, - patients with history of acute myocardial infarction, severe hypersensitive reactions and emesis). [42]. hypotension, decompensated heart failure or renal impairment have also contraindication to this method; Similar to SPECT, it had been shown that CMR can have long- - pregnant women or patients who are unable to cooperate term prediction values. Newer technology in CMR measures to the breath-hold instructions are not able to have CTCA. GLS (global longitudinal strain), this marker can be an [47] independent predictor for long-term major adverse cardiac events (MACE): heart failure hospitalization, myocardial The method involves usage of a bolus of contrast injected infarction, sustained ventricular tachycardia or death, in i.v., and after that realizing a coronary angiogram with pacients with known or suspected coronary artery disease. complementary ECG gating. The ACCURACY trial showed That means CMR can identify patients with high risk of that CTCA in comparison to ICA (invasive coronary having dangerous adverse events in the near future because angiography) had similar performances in measurements of CAD. [43] (CTCA sensitivity – 95% vs. 94%, CTCA specificity 83% vs. 83%, CTCA positive predictive value – 64% vs. 48% and CTCA Also, the newest data shows that CMR with quantitative negative predictive value 99% vs. 99%) for diagnosis of CAD myocardial perfusion mapping can detect coronary with 50%/70% stenosis. [2] microvascular dysfunction separately from CAD, with high AUC-ROC prediction values (0.95 on vessels with MVD) with Although the main issue in this non-invasive technique is high sensitivity (90%) and specificity (89%), almost usage of radiation and scan preparation, another problem is comparable with invasive procedures. [44] that presence of heavy calcification (objectively measured by an Agatston score > 400) in case of patients with severe More powerful magnets (3.0 Tesla), although not so widely CAD lowers the specificity, by creating beam hardening available, used on CMR machines, have a net superiority artefacts and excessive image noise. [48] 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 Analysis of outcome data, such as in the PROMISE trial, specificity (100% vs. 61.9%). [45] showed that patients with suspected CAD who did CTCA had in long-term observation, fewer catheterizations than Computed tomography patients who were functionally tested (using exercise Multidetector row CT systems used in cardiac CT are electrocardiography, stress echocardiography or nuclear sufficient enough to visualize coronary anomalies, although stress testing) although these patients hadn’t any this last method is preferable for measuring coronary improvement in clinical outcome. [49], and also the SCOT- anatomy and pathology occurring in this matter. There are HEART trial showed that usage of CTCA reduced fatal and two methods of using CT in the benefit of diagnosis for CAD: non-fatal myocardial infarction but not significantly in calcium scoring and CTCA (coronary computed tomography patients with suspected CAD. [50] angiography). Improving the current performance in CTCA is possible. One

method is measuring tthe fractional flow reserve (CTFFR). stenosis and raising overall diagnostic accuracy (from 71% to Although it is highly time-consuming and requires computer 85%). [54] modeling, data shows that usage of CTFFR in CTCA is beneficial, increasing the diagnostic accuracy in comparison CONCLUSION to standard CTCA. [51] Currently, non-invasive techniques used to diagnose stable Additional usage of β-blockade and nitroglycerin before the coronary artery disease have a very high accuracy and newer exam seem to increase the diagnostic performance [52] and methods seem to be comparable to the gold-standard. The newer data show that CTFFR-CTCA is a safe alternative to ICA majority of the methods discussed have an optimal with a significantly lower rate of ICA in comparison to performance for patients with PTP between 15-85%, and the functional testing (61% cancelling rate), therefore lowering future of diagnosis for these patients seem to involve less the clinical cost and having the same clinical outcomes. [53] invasive measures and less radiation by improving the current devices and by usage of machine-learning Machine-learning (based on a deep learning model) in algorithms. CTFFR-CTCA seems to also make better the standard procedure, by reclassifying patients with nonsignificant

References:

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

Article received on April 3, 2019 and accepted for publishing on June 23, 2019. 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 factors. It is associated with liver cirrhosis, autoimmune disease, connective tissue disorders and collagen vascular Gastric antral vascular ectasia (GAVE) or “watermelon disorders (eg, systemic sclerosis, Sjogren syndrome), chronic stomach” is a relatively rare cause of gastrointestinal (GI) renal failure, bone marrow transplantation, acute myeloid bleeding that mainly affects women aged 70 years and older. leukemia and heart disease. The incidence is estimated to be aproximately 4% of upper GI bleeding [1]. The term "watermelon stomach" is derived Frequently GAVE patients have chronic GI bleeding, but from the characteristic endoscopic appearance of sometimes it can cause severe acute life-threatening longitudinal rows of flat, reddish stripes radiating from the bleeding especially in elderly with multiple chronic medical pylorus into the antrum that resemble the stripes on a illnesses [2]. watermelon [2]. GAVE is typically located in the gastric antrum; however, it It usually presents as occult bleeding with chronic iron may be also found rarely in other areas of the GI tract, deficiency anemia. Even though GAVE was first diagnosed including cardia, duodenum, jejunum, and rectum. The about six decades ago, its etiopathogenesis has not been fully established yet, with many hypotheses proposed such as mechanical stress, hormonal factors, and autoimmune 1 Carol Davila University Emergency Central Military Hospital, Bucharest, Romania 2 Carol Davila university of Medicine and Pharmacy, Faculty of Corresponding author: Ailenei Mihaela General Medicine, Bucharest, Romania [email protected] 3 Titu Maiorescu University, Bucharest, Romania

involvement of the proximal part of the stomach is very rare APC has been found to be equally effective in the treatment and commonly located within a diaphragmatic hernia. of GAVE and is superior to ND:YAG laser in cost, convenience and complication rates(4). At endoscopy, GAVE may appear as 2 types. First type is the diffuse punctuate lesions in the antrum typically seen in The non-ablative treatment options is the endoscopic band male patients with cirrhosis and commonly accompanied by ligation. EBL was firstly reported as the treatment for acute bleeding. Second one is the red lesions organized in refractory GAVE in the patients who failed other treatment stripes radially departing from the pylorus, known as modalities such as APC or hormonal therapy by Sinha et al. “watermelon stomach”, mostly common in females with [5] connective tissue diseases and usually present with occult Endoscopic band ligation has been reported as an alternative bleeding [1]. effective endoscopic therapy and the rate of complication is Histopathologically, GAVE is characterized by vascular low in comparison with those reported for APC in ectasia, spindle cell proliferation, and fibrohyalinosis. retrospective studies [6]. Immunohistochemical staining for CD61, a platelet marker, A case series of 9 patients reported by Wells et al also further confirms a diagnosis of GAVE [3]. showed superiority of EBL over endoscopic thermal therapy, Over the years, treatment for gastric antral vascular ectasia which were APC and bipolar thermal probe therapy, for the (GAVE) has continued to evolve and the number of available rate of re-bleeding, duration of hospitalization and post treatments has continued to increase, including surgical, procedure transfusion. The complications reported for this medical and endoscopic therapies procedure were very small. Band ligation was prefered as the first line treatment regarding of the extensive Medical therapy has not clearly shown satisfactory results. involvement of the lesion in the patients. According to the Multiple drugs, such as hormonal (estrogen-progesterone) result of the treatment mentioned above, endoscopic band therapy, steroids, octreotide and tranexamic acid, have been ligation could be considered as first line treatment options tried to control GAVE-related bleeding. After all, no one has for the GAVE patients especially for extensive area of clearly shown satisfactory results in order to consider involvement. [7] medical therapy as a valid alternative to an invasive approach. A recent prospective study showed endoscopic improvement with the use of endoscopic band ligation in Endoscopic therapies have rapidly become the first line 91% of the patients, with a significant improvement in the therapy with argon plasma coagulation (APC) as the most hemoglobin and ferritin levels. Band ligation in GAVE has common used method and more recently with been associated with transient abdominal pain in a minority radiofrequency ablation system (RFA) using Halo90 catheter of the patients, but no major complications have been and endoscopic band ligation (EBL). Both of them have been reported in the literature. [9] shown to be safe and effective for GAVE treatment. The latter two have been utilized in treatment of severe, diffuse, Some studies suggest that the number of sessions required APC refractory GAVE. The clinical outcomes of ablative for GAVE eradication is inferior when using EBL compared to therapy such as APC treatment or HALO90 system were APC, resulting in inferior health care costs. However, reported as 80%-100% success rate. randomized controlled trials are lacking to determine whether EBL is more cost effective than APC as the primary Other therapies include Nd:YAG (neodymium:yttrium- endoscopic therapy for GAVE. [9, 10] aluminum-garnet) laser coagulation, but with a higher risk of perforation given the deeper thermal effect. Endoscopic Although initial reports of these endoscopic modalities are sclerotherapy, heater probe, cryotherapy have also been encouraging, well-performed, larger, prospective studies are described in the literature. For unresponsive cases to needed before providing any definitive conclusion. endoscopic therapy, surgery with antrectomy can be considered but carries a high surgical risk, especially in the CASE PRESENTATION cirrhotic patients. Clinical data APC is most commonly used method, but has been We present a case of a 57-year-old female, diabetic with associated with sepsis, post-APC bleeding, gastric outlet multiple microvascular complications – diabetic polineuro- obstruction and increased incidence of hyperplastic polyps’ pathy and chronic renal disease, hypertensive, with formation. It is needed multiple sessions of APC to reduce moderate hypochromic microcytic anaemia and a positive bleeding episodes and/or decrease transfusion dependence.

52 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine fecal occult blood test (FOBT), already in treatment with iron Histopathology data therapy who presented for abdominal pain, fatigability, Ulcer post argon plasma coagulation biopsy performed phisical astenia and arthralgias. She denied no change in showed modifications of chronic inactive gastritis, but GAVE weight, bowel pattern, or stool color. The physical was not confirmed on biopsy. examination revealed paleness of the skin and mucosa and otherwise unremarkable. Evolution

Laboratory data After two months and with iron therapy, the hemoglobin level was normalised (12.7 g/dL) with low mean corpuscular Labs indicates a moderate hypochromic microcytic anaemia volume and mean corpuscular hemoglobin. At the (hemoglobine level – 9.4 g/dL, mean corpuscular volume – endoscopic examination the macroscopic appearance 70.2 fL, hematocrit – 31.1%, mean corpuscular hemoglobin persisted with multiple friable hypertrofic and nodular antral – 21.2 picog and sideremia – 26 microg/L. vascular ectasia and duodeno-gastric reflux. Endoscopy At 3 months follow-up, hemoglobin level mantained in the Superior digestive endoscopy showed hypertrofic gastric normal interval (13.5 g/dL), but the endoscopic appearing antral vascular ectasia with mucosal eryhema, friability and was worst, with larger, friable, with edema and hypertrofic visible small vessels extending radially in linear rows gastric atral vascular ectasia (Figure 1). We decided to apply throughout the antrum and a duodeno-gastric reflux. She 6 elastic bands on the biggest lesions with success (Figure 2). underwent serial argon plasma coagulation treatments and No complications of the procedure were reported, and the a second gastroscopy was performed next day which patient was discharged after 24h. showed post argon plasma coagulation ulcers which were biopsied.

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). DISCUSSION The upper endoscopy revelead small hyperemic antral GAVE is a poorly understood entity, of unknown etiology, circumferential disposed lesions with no signs of bleeding and an increasingly identifiable cause of chronic iron and no hypertrophy, with almost complete eradication of deficiency anemia. The pharmacological management of GAVE (Figure 3).

GAVE had only poor results, so the mainstay of GAVE applies high-frequency energy into tissue to cause thermal management remains endoscopic therapy. effects, which has been used successfully to treat GAVE with an effective transient response, but primary failure rates of Figure 3. Endoscopic appearance 2 months after endoscopic band therapy of up to 14% have been reported. Some authors ligation 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 Figure 4. Suggested flow chart for treatment algorithm [14]. that EBL may be useful in the treatment of GAVE, to avoid GAVE: Gastric antral vascular ectasia; APC: Argon plasma the high recurrence rate after APC. coagulation; RFA: Radiofrequency ablation; EBL: Endoscopic band ligation. 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 APC is a modality of non-contact electrocoagulation that multimodal therapy.

References:

1. Dulai GS, Jensen DM, Kovacs TO, Gralnek IM, Jutabha R. Pathol. 2010;34:494-501. Endoscopic treatment outcomes in watermelon stomach patients 4. Naga M, Esmat S, Naguib M, Sedrak H. Long-term effect of argon with and without portal hypertension. Endoscopy. 2004;36:68-72. plasma coagulation (APC) in the treatment of gastric antral vascular 2. Selinger CP and Ang YS. Gastric antral vascular ectasia (GAVE): ectasia (GAVE) Arab J Gastroenterol. 2011;12:40–43. An update on clinical presentation, pathophysiology and treatment. 5. Sinha SK, Udawat HP, Varma S, Lal A, Rana SS, Bhasin DK. Digestion 2008; 77: 131–137 Watermelon stomach treated with endoscopic band ligation. 3. Westerhoff M, Tretiakova M, Hovan L, Miller J, Noffsinger A, Gastrointest Endosc. 2006;64:1028–103 Hart J. CD61, CD31, and CD34 improve diagnostic accuracy in gastric 6. Sato T, Yamazaki K, Akaike J. Endoscopic band ligation versus antral vascular ectasia and portal hypertensive gastropathy: an argon plasma coagulation for gastric antral vascular ectasia immunohistochemical and digital morphometric study. Am J Surg associated with liver diseases. Dig Endosc 2012; 24: 237-242

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7. Wells CD, Harrison ME, Gurudu SR, Crowell MD, Byrne TJ, 11. S.M.A. Nakamura, H. Konishi, I. Oi, K. Shiratori, S. SuzukiLong- Depetris G, Sharma VK. Treatment of gastric antral vascular ectasia term follow up of gastric antral vascular ectasia treated by argon (watermelon stomach) with endoscopic band ligation. Gastrointest plasma coagulation, Dig Endosc, 18 (2006), pp. 128-133 Endosc. 2008;68:231–236. 12. E. Swanson, A. Mahgoub, R. MacDonald, A. ShaukatMedical and 8. Kumar R, Mohindra S, Pruthi HS. Endoscopic band ligation: a endoscopic therapies for angiodysplasia and gastric antral vascular novel therapy for bleeding gastric antral vascular ectasia. ectasia: a systematic review, Clin Gastroenterol Hepatol, 12 (2014), Endoscopy. 2007;39 Suppl 1:E56–E57. pp. 571-582 9. S. Zepeda-Gomez, R. Sultanian, C. Teshima, G. Sandha, S. Van 13. Prachayakul V, Aswakul P, Leelakusolvong S. Massive gastric Zanten, A.J. Montano-Loza, Gastric antral vascular ectasia: a antral vascular ectasia successfully treated by endoscopic band prospective study of treatment with endoscopic band ligation as the initial therapy. World J Gastrointest Endosc 2013; 5: ligation,Endoscopy, 47 (2015), pp. 538-540 135–137. 10. J. Keohane, W. Berro, G.C. Harewood, F.E. Murray, S.E. 14. Tasnia Matin, Mohammed Naseemuddin, Mohamed Shoreibah, PatchettBand ligation of gastric antral vascular ectasia is a safe and Peng Li, Kondal Kyanam Kabir Baig, Charles Mel Wilcox, Shajan effective endoscopic treatment, Dig Endosc, 25 (2013), pp. 392-396 PeterWorld J Gastrointest Endosc 2018 January 16; 10(1): 30-36.

Article received on May 28, 2019 and accepted for publishing on June 23, 2019. 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 being present inside the microcirculation.

Embolism represents the motion through circulatory blood Fat embolism was first described by Zenker in 1862 in the flow of a material which is not present in blood in normal case of a railroad worker who died of crushing injuries. In conditions and its subsequent lodging inside the blood 1873 Bergmann diagnosed fat embolism in a living patient vessels. In the case of fat embolism, the material carried who had suffered a fracture of the femoral bone [1, 2]. through the blood is represented by fat particles that reach The causes of fat emboli formation are multiple, both the level of microcirculation. Fat embolism syndrome traumatic and non-traumatic. The most frequent traumatic represents the systemic manifestation of the fat particles causes are: long bone fractures, orthopedic procedures, soft tissue trauma (fat tissue laceration), liposuction and mastectomy, neurosurgical interventions. Non-traumatic 1 Bihor County Forensic Service, Oradea, Bihor, Romania 2 County Clinical Emergency Hospital Cluj-Napoca, Clinical causes include: acute pancreatitis, extensive burns, Department of Dermatovenerology diabetes, fatty liver due to diets rich in extrinsic fats and oils 3 County Emergency Hospital of Oradea, Department of Urology, [2, 3]. Exceptionally, fat embolism has been observed in Oradea, Romania 4 University of Oradea, Faculty of Medicine and Pharmacy, cases of hepatic steatosis (in alcoholics and diabetic patients Department of Morphological Disciplines, Oradea, Romania with hepatic damage) due to the destruction of hepatocytes 5 Grigore T. Popa University of Medicine and Pharmacy of Iasi, and subsequent release of fat particles [4, 5]. Romania, Department of Legal Medicine 6 University of Oradea, Faculty of Medicine and Pharmacy, Department of Medical Disciplines Corresponding author: Andreea A. Hleșcu 7 Institute of Legal Medicine of Iași, Romania [email protected]

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Fat embolism occurs in 90% of patients who have suffered a Surgical intervention was performed to evacuate the dura trauma, but only 2-5% of them develop the fat embolism mater hygroma 6 days after the admission. Evolution was syndrome; particularly at risk are those with fractures of the initially favorable. On the 4th postoperative day, the patient long bones. It is difficult to estimate the duration of this developed a febrile syndrome. Laboratory analysis syndrome because the symptoms are often subacute or highlighted: elevated leucocyte count (13.390 of which masked by other symptoms of trauma [2, 3]. 11.270 neutrofils); elevated serum amylase (225 U/L); lowered erythrocyte count (3.83 milion); hematocrit levels Post-mortem studies have shown a different but a very high as low as 40.08 %; low thrombocytes count (137.700); incidence of fat embolism. Thus, a study by Behn C. et al. on increased level of the liver enzyme AST to 48 U/L; low 527 autopsies demonstrated the presence of fat embolism creatinine serum levels (0.69 mg/dl) and reduced glomerular in 92 of these [6]. Another study conducted by Hiss et al. in filtration rate to 85 mil/min/1.73 m2. The next day the 1996, on 53 victims of aggression followed by death, showed patient suffered cardiorespiratory arrest that did not a high incidence of fat embolism. All the subjects studied respond to resuscitation maneuvers, followed by death. The were young, male, victims of aggressions, suffering severe forensic autopsy was performed. The external examination trauma 24 hours before death. In thirty two cases the of the body showed: multiple injuries denoting violence such presence of fat embolism was observed in the main organs, as ecchymoses and abrasions; signs of medical treatment at with no other obvious cause of death. The authors of the the level of the skull, i.e. recent surgical incision and an old study hypothesized that the source of fat embolism was the whitish scar. The internal examination showed: on the head, mechanical disintegration of the subcutaneous adipose 2 craniotomy areas, one of them being recent, subarachnoid tissue [7]. hemorrhage, areas of flaccid cerebral structure, small In cases of fat embolism there is a poor correlation between petechial hemorrhagic areas disseminated throughout the post-mortem and clinical findings. This discrepancy brain. The examination of the lungs showed: pulmonary ultimately gave rise to the concept of "iceberg effect of fat stasis and edema, and areas of pulmonary condensation. embolism" [8- 12]. This justifies, as well as cases with a Fragments of brain and lungs were harvested during autopsy insufficiently outlined clinical picture for a particular and subsequently examined by optic microscopy using the pathology, or a clinical picture that cannot explain the Sudan III staining. The microscopic examination revealed fat occurrence of death, the importance of forensic autopsy and emboli in the brain and lungs. Following the postmortem postmortem laboratory investigations (histopathological macroscopic and microscopic examination we established and toxicological) in order to establish the thanatogenerator that the cause of death was the fat embolism syndrome. mechanism and the causal link between trauma / illness and Case no. 2 death, and ultimately the legal nature of the case, i.e. suicide, accident or homicide [13- 19]. Male, 54 years old, was admitted to the hospital with the diagnosis of: head trauma (subarachnoid hemorrhage, MATERIALS AND METHODS fracture of the left temporal bone with extension to the mastoid bone), face trauma (fracture of right jaw, We present three cases of trauma in which the cause of comminuted fracture of the nose) and chest trauma (left death was the fat embolism syndrome. All the cases are pneumothorax, multiple rib fractures). characterized by a rapid clinical deterioration leading to death, so that a clinical diagnosis of fat embolism syndrome The patient was hospitalized for 35 days, during which could not be established antemortem. multiple pleurotomies and bronchoscopies were performed. Laboratory examinations showed: increased leucocyte count Case no. 1 (25.170 of which 21.100 neutrofils); low red blood cell count Male, 72 years old, chronic alcohol consumer, with past (2.612 milions); low hematocrit (21.240 %); low hemoglobin medical history of left femoral fracture and right sided level (7.793 g/dl); normal thrombocyte count; increased craniotomy, is admitted to hospital for head trauma. At the level of AST (103 U/L); increased serum creatinine (4.28 time of admission physical examination revealed multiple mg/dl); increased GGT levels (93 U/L) and reduced ecchymoses, pain at the pelvic level, lower limbs and glomerular filtration rate (10.8 mil/min/1.73 m2). Clinical abdomen. Clinical and paraclinical investigations established evolution was initially favorable. On day 34 after admission the following diagnosis: minor craniocerebral trauma, facial the patient developed a feverish syndrome. The next day he trauma, posttraumatic subarachnoid hemorrhage, dura suddenly suffered cardiorespiratory arrest, followed by mater hygroma, abdominal contusion, pelvic contusion. death. A forensic autopsy was performed. The external examination of the cadaver revealed bruises and signs of

recent medical treatment. The internal examination occurrence were met. However, in none of the cases the showed: linear head fracture, subdural hematoma under diagnosis was clinically established antemortem. The partial resorption, small petechial hemorrhagic areas in the examination by optic microscopy of the fragments of brain brain, pulmonary edema, and areas of pulmonary and lungs collected during autopsy and stained with Sudan condensation. Fragments of organs were harvested (brain, III showed in all the cases the fat microemboli in the form of lung) and examined by optic microscopy using Sudan III orange globes disseminated throughout the fields examined staining. Following the macroscopic and microscopic microscopically (figures 1-4) and allowed the postmortem examinations we concluded that the cause of death was the diagnosis of fat embolism. Therefore, in all three cases fat embolism syndrome. presented, the results of the histopathological examination of the fragments harvested from the brain and the lungs Case no. 3 during the autopsy were essential for determining the cause Male, 20 years old, victim of a traffic accident, was admitted of death. to the hospital with the diagnosis of: polytrauma due to road traffic accident, major craniocerebral trauma with diffused Figure 1: Microscopic aspect of brain tissue cerebral edema, multiple rib fractures, fracture of the left Sudan III stain x 40 (ice exam) 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 Figure 2: Microscopic aspect of lung tissue U/L); increased serum creatinine (2.43 mg/dl); increased Sudan III stain x 20 (ice exam) 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 Figure 3: Microscopic aspect of lung tissue macroscopic autopsy findings and histo-pathological Sudan III stain x 40 (ice exam) 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

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Figure 4: Microscopic aspect of lung tissue From a clinical point of view, Gurd and Wilson have Sudan III stain x 10 (ice exam) 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 DISCUSSION platelet values (more than 50% of the value upon Fat embolism occurs due to the mobilization of fat cells or admission); increased erythrocyte sedimentation rate fat released by them, followed by their direct penetration (greater than 71 mm per hour); fat globules present in the into open blood vessels or lymphatic channels. Most emboli sputum; emboli present in the retina; tachicardia; fever; have a diameter of 15 to 40 μ; the fat emboli in the lungs are renal insufficiency; sudden thrombocytopenia. According to generally larger than those in the large arteries of the Gurd and Wilson the diagnosis of fat embolism can be systemic circulation [11]. established if either one major criterion and 4 minor criteria or 2 major criteria are met [21]. Several theories are mentioned in the literature to explain the pathogenesis of the fat embolism [20]. Lindeque suggested that the criteria of Gurd and Wilson may under-diagnose the syndrome, and proposed the following The mechanical theory shows that mobilization of fat criteria based on respiratory parameters: Pao2 kPa of less particles occurs due to trauma to the bones or soft tissues. than 8Fio2 0.21; Paco2 kPa or pH of less than 7.3 or more As a consequence, the fat particles released by the trauma than 7.3; respiratory rate greater than 35 breaths/min−1 enter the venous circulation from where they reach the even after adequate sedation; increased breathing efforts lungs, where the majority remains, but some of them can showed by: dyspnea, use of accessory muscles, tachycardia also pass into the systemic circulation, reaching other and anxiety [22]. Any patient with a fractured femur and/or organs. tibia, presenting one or more of these criteria, was The biochemical theory, also known as the emulsion diagnosed with fat embolism syndrome. These criteria led to instability theory, is mostly useful in explaining the non the diagnosis of fat embolism syndrome in 29% of patients traumatic fat embolism. in a series of 55, which is higher than other series, especially since this study excludes patients with thoracic lesions, The intravascular coagulation theory holds that in stressing where some of Lindeque's clinical signs may appear in the conditions, substances that activate disseminated intra- absence of fat embolism [22]. vascular coagulation and aggregation of fat particles are released. Petechial eruption is considered a pathognomonic clinical sign for fat embolism syndrome. It may occur in about 60% The toxic trauma theory claims that small blood vessels are of patients, usually on the conjunctiva, on the oral mucous affected by high concentrations of fatty acids in the plasma membrane and on the skin of the neck and shoulders. This leading to increased vascular permeability. distribution can be explained by the drops of fat that The mechanical theory is based on the concept of the accumulate in the aortic arch before the independent mobilization of fatty bone marrow from the long bones embolization at skin level through the subclavian and carotid diaphysis. In the cases presented by us, only one patient vessels [20, 23-25]. The factors contributing to the petechial suffered a recent fracture of the femur. In the other two eruption are: stagnation of blood, loss of coagulation factors cases we have to consider the trauma of soft tissues and platelets, and damage to the endothelial walls due to (hypodermic tissue) as the cause of the fat embolism, by free fatty acids (FFA) leading to rupture of capillaries [25]. noting that in both cases multiple ecchymoses were In the vast majority of cases, the fat embolism remains observed on the skin. asymptomatic, and the fat emboli are dispersed into small cells and phagocyted by macrophages or embedded in

hepatic cells [26, 27]. Thus, many cases remain undiagnosed the lung and brain tissues. Of the cases presented only one before death. suffered a recent fracture of the femur; another presented in addition to trauma paraclinical changes suggestive of In the three cases presented, the symptomatology before acute pancreatitis as a contributing factor; none had cardiac death was poor and unspecific (febrile syndrome, malformations that could explain the paradoxical fat tachycardia, tachypnea), and remained undiagnosed. The embolism in the brain; all of the cases showed multiple diagnosis of fat embolism syndrome was established only lesions of the subcutaneous tissue and death occurred after performing the autopsy, and the histopathological shortly after the initial trauma or after surgical interventions. examination of the brain and lung fragments stained specifically with Sudan III. Therefore, for post mortem Death due to fat embolism can fall into the category of diagnosis of fat embolism syndrome, it is essential to violent or non-violent deaths. Regardless of the cause of fat perform a histopathological examination with special stains embolism, from forensic point of view the fat embolism is that highlight the presence of fat emboli in the tissues and considered a complication that leads to a secondary causal organs. relationship; in other words between the trauma/ initial pathology and death an intermediate link is inserted In the cases presented in this paper, fat embolism at the represented by a complication (the fat embolism) which is pulmonary and cerebral level was observed. According to connected to a greater or lesser extent to the initial trauma/ literature, brain and lung localizations are the most pathology [28-30]. important, although in most cases pulmonary fat embolism remains clinically asymptomatic. In order to be able to certify CONCLUSION fat embolism as the cause of death, it is necessary for histopathological examinations to find fat emboli on a large From forensic point of view, the diagnostic certainty in part of the examination fields. The gravity of the posttraumatic lesions is a priority objective. From the consequences of pulmonary embolism also depends on the diagnosis it is possible to reconstruct the thanatogenerator size and amount of fat emboli, as well as whether or not they mechanism and finally it can be useful to respond to the legal pass into the systemic circulation to the lung. aspects of the case, i.e. the causal relationship between trauma and death. In the brain, emboli produce small petechial hemorrhages, areas of ischemic necrosis and hemorrhage or necrosis and In the case of trauma with reduced thanatogenerator demyelination. Cerebral embolism is considered in literature potential, which usually evolve without complications, the as a paradoxical event, because it requires the presence of occurrence of fat embolism syndrome followed by death cardiac atrial septal defects in order to be explained. In the must be appropriately explained so that the case can be presented cases, there was no autopsy finding that showed properly framed from a legal point of view. It is important to neither atrial or ventricular septal defects nor patent arterial emphasize that the histopathological examination using canal that could explain the cerebral fat embolism. An specific stainings, such as Sudan III, has a fundamental and explanation of the pathophysiological mechanism which incontestable role in the diagnosis of fat embolism and in determined the cerebral embolism could not be found in this estimating its gravity, and therefore, its implication in the study. occurence of death.

The cause of death in all the three cases presented in this paper was the fat embolism. The diagnosis was established Conflict of interest: The authors declare that there is no conflict of with certainty only after autopsy, by a histopathological interest. examination which revealed the presence of fat emboli in

References:

1. Von Bergmann E. Ein fall todlicher fettenbolic. Berl Klin 4. Diaconu C, Bălăceanu A, Costache C. Prevalence of hypoxic Wochenscher. 1873; 10:385. hepatitis in heart failure patients. J Hepatol. 2014; 60, Suppl 1: S515. 2. Taviloglu K, Yanar H. Fat embolism syndrome. Surgery today. The International Liver Congress, 49th annual meeting of the 2007; 37(1):5-8. European Association for the Study of Liver, April 9-13, 2014, London, UK. 3. Bartoş D, Diaconu C, Bădilă E, Daraban AM. Old and new in lipid lowering therapy: focus on the emerging drugs. Farmacia. 2014; 5. Popa AR, Vesa CM, Uivarosan D, Jurca CM, Isvoranu G, Socea B, 62(5):811-823. Stanescu AM, Iancu MA, Scarneciu I, Zaha DC. Cross Sectional Study

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Regarding the Association between Sweetened Beverages Intake, 17. Judea-Pusta C, Rusu A, Camarasan A. Suicide by abdominal Fast-food Products, Body Mass Index, Fasting Blood Glucose and wounds suggesting seppuku: Case reports from Romania and an Blood Pressure in the Young Adults from North-western Romania. international literature review. Aggres Viol Behav. 2019; 47:68-73. Rev Chim-Bucharest. 2019; 70(1):156-160. https://doi.org/10.1016/j.avb.2019.03.006. 6. Behn C, Höpker WW, Püschel K. Fat embolism-a too 18. Iorga M, Dondas C, Ioan BG, Toader E. Job Satisfaction among infrequently determined pathoanatomic diagnosis. Forensic Physicians in Romania. Revista de Cercetare si Interventie Versicherungsmedizin. 1997; 49(3):89-93. Sociala. 2017; 56: 5-18; 7. Hiss J, Kahana T, Kugel C. Beaten to death: why do they die? J 19. Hanganu B, Crauciuc D, Petre-Ciudin V, Velnic, AA, Manoilescu Trauma Acute Care Surg. 1996; 40(1):27-30. I, Ioan BG. Domestic Violence in the Postmodern Society: Ethical and 8. Ioan B, Alexa T, Alexa ID. Do we still need the autopsy? Clinical Forensic Aspects. Postmodern Openings. 2017; 8(3): 46-58 diagnosis versus autopsy diagnosis. Rom J Leg Med. 2012; 20(4):307- 20. Kwiatt ME, Seamon MJ. Fat embolism syndrome. Int J Crit Illn 312. Inj Sci. 2013; 3(1):64-68. 9. Roman G, Bala C, Creteanu G, Graur M, Morosanu M, Popa AR, 21. Gurd AR, Wilson RI. The fat embolism syndrome. J Bone Joint Pircalaboiu, L, Radulian G, Timar R, Cadariu AA. Obesity and health- Surg Br. 1974; 56 B: 408–416. related lifestyle factors in the general population in Romania: a cross 22. Lindeque BG, Schoeman HS, Dommissen GF, Boeyens MC, Vlok sectional study. Acta Endo (Buc). 2015; 11(1):64-71. AL. Fat embolism syndrome: A double blind therapeutic study. J 10. Juncar M, Popa AR, Baciut MF, Juncar RI, Onisor-Gligor F, Bran Bone Joint Surg Br. 1987; 69:128–131. S, Baciut G. Evolution assessment of head and neck infections in 23. Daina L, Carp G, Neamțu C, Venter A, Armean A. Antibiotherapy diabetic patients - A case control study. J Craniomaxillofac Surg. in hospital – between the efficiency and quality of medical services. 2014; 42(5):498-502. The role of the Drug Committee. Farmacia. 2015; 63(3):407-412. 11. Chan KM, Tham KT, Chiu HS, Chow YN, Leung PC. Post-traumatic 24. Mellor A, Soni N. Fat embolism. Anaesthesia. 2001; 56(2):145- fat embolism-its clinical and subclinical presentations. J Trauma. 154. 1984; 24(1):45-49. 25. Tachakra SS. Distribution of skin petechiae in fat embolism rash. 12. Velnic AA, Hanganu B, Petre-Ciudin V, Ioan BG. Clinical diagnosis The Lancet. 1976; 307(7954):284-285. versus autopsy diagnosis in head trauma. Forensic Science 26. Jaffe FA. Petechial hemorrhages. A review of pathogenesis. Am International. 2017; 277 (Suppl. 1): 209 J Forensic Med Pathol. 1994; 15(3):203-207. 13. Judea-Pusta CT, Muțiu G, Pașcalău AV, Buhaș CL, Ciursaș AN, 27. Juncar M, Popa AR, Lung T, Onisor F. Septic metastases of Nistor-Cseppento CD, Bodea A, Judea AS, Vicaș RM, Dobjanschi L, suppuration of odontogenic origin. Chirurgia. 2011; 106(3):359-364. Pop OL. The importance of the histopathological examination in lethal acute intoxication with ethylene glycol. Case report. Rom J 28. Buhas CL, Mihalache G, Judea-Pusta CT, Buhaș B, Jurcă MC, Morphol Embryol. 2018; 59(3):965-969. Iovan C. Lethal cranio-cerebral traumatism resulting through a very rare mechanism. Rom J Leg Med. 2018; 26(3):249-253. 14. Pusta CT, Mihalache G, Buhas C, Pop O. A rare case of cardiac fibroma in a death truck driver. Rom J Leg Med. 2015; 23(4):247- 29. Buhas C, Mihalache G, Buhas B, Bungău S. The difficulty in 250. establising the generating mechanism of cranial and vertebral lesions in a cadaver partially skeletonised. Rom J Leg Med. 2016; 15. Mekeres F, Buhas C. Spontaneous human combustion, 25(4):300 – 303. homicide, suicide or household accident. Rom J Leg Med. 2016; 24(1):11-13. 30. Hanganu B, Velnic AA, Manoilescu IS, Ioan BG. Challenges to Forensic Medicine in the Postmodern Era- the Impact of the New 16. Buhaş C. Psychic family violence and pathological jealousy with Technologies. Postmodern Openings. 2017; 8(3): 12-23. tragic consequences: Homicide. Aggres Viol Behav. 2013; 18(4):434 – 435.

Article received on May 13, 2019 and accepted for publishing on June 23, 2019. 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 CASE REPORT

Development of thyroid gland starts by the pharyngeal We present the case of a 50 years old female patient with epithelium thickening floor which later forms a diverticulum chronic renal failure of unknown etiology (probably which, in its development is pushed caudally. The descent secondary to hyper blood pressure), with Graves Disease (in path is usually anterior to hyoid bone but it can also be treatment with antithyroid drugs for about 1 year) who was posterior or through the hyoid bone and ends on the admitted in our department after she has initially presented anterior surface of the first few tracheal rings. in an ENT department (Otolaryngology) for the investigation of a tumoral mass located in the midline upper neck. At that This primitive steam that connects primordium with moment physical exam revealed a 2/3 cm mass between the pharyngeal floor becomes thyroglossal duct. Until the hyoid bone and the thyroid cartilage, mobile on swallowing, second month of gestation thyroglossal duct devolve, painless spontaneously and on palpation, covered by normal leaving at its place a small lump – the foramen cecum, at the skin. IRM exam revealed a bilobate lesion 2.9/1.1 cm, very unification of third medium with posterior third of the well encountered, in close relationship with the adjacent tongue, but portions of the duct associated with thyroid muscles and the hyoid bone, without any other pathological tissue can persist at any site between tongue and thyroid [1, changes on the structures of the anterior neck: no enlarged 2]. lymph nodes. There were no reference about thyroid gland Cells in the lowest portion of the thyroglossal duct which on the IRM report. The IRM conclusion was: expansive comprises normal thyroid tissue differentiates in forming anterior cervical soft tissues tumoral mass. Surgical excision pyramidal lobe of the thyroid gland. Pyramidal lobe often of the tumoral mass and simultaneous removal of the central comes out from the thyroid isthmus, but can also come from portion of the hyoid bone (Sistrunk procedure) was the medial side of one or both thyroid lobes [1]. The performed and the pathology report showed papillary pyramidal lobe is thought to be present in 15-75% of the thyroid carcinoma arising from thyroglossal duct. In our general population [1, 3]. Thyroglossal duct fails to involute department, three months later, thyroid ultrasound showed in approximately 7% of the population [4]. hypoechoic, inhomogeneous echotexture suggestive for chronic autoimmune process, hypoechoic nodule with Many remnants of thyroglossal duct are never detected discrete Doppler flow, without hypoechoic halo located at clinically (2) and malignant transformation is uncommon [5]. the connection of the right thyroid lobe with isthmus and two micro lymph nodes with intense Doppler flow, without 1 C.I. Parhon National Institute of Endocrinology, Bucharest, hilum of 0.5/0.4 cm and 0.7/0.4 cm located anterior of the Romania 2 St Maria General Hospital, Bucharest, Romania larynx. Tumoral mass previously removed in the ENT 3 Carol Davila University of Medicine and Pharmacy, Bucharest, department was reviewed and the pathology report showed Romania tumoral multilobulated pyramidal thyroid lobe with pattern

62 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine of solid and sclerosant variant of papillary carcinoma, report also showed reactive lymphadenopathy and post infiltrative into fibro conjunctive, adipose and muscular surgery staging was pT3N0. adjacent tissue (Figure 1 and Figure 2) and areas of micro angioinvasion of the capsule (Figure 3). Figure 4: Embedded thyroid isthmus focus of papillary thyroid carcinoma (x20 HE) Figure 1: Papillary carcinoma infiltrative into fibroconjunctive, adipos and muscular adjacent tissue (x20 HE)

Figure 5: Marginal invasion of the capsule (x100 HE)

Figure 2: Papillary carcinoma infiltrative into fibroconjunctive adipose and muscular adjacent tissue (x40 HE)

Figure 6: Microangioinvasion of the capsule (x100 HE)

Figure 3: Micro invasion of the capsule (x200 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 In this context, we decided total thyroidectomy (also as a the body. Because of the association of BRAF mutation with treatment for Graves Disease) with dissection of central papillary carcinoma of the pyramidal thyroid lobe, genetic lymph nodes compartment. Histopathology report revealed testing of BRAF gene were performed and they were embedded thyroid isthmus focus of papillary thyroid negative for somatic mutations in the 600 codon. carcinoma 0.7/0.6 cm with tumoral pattern similar to that of tumoral pyramidal lobe previously removed (Figure 4), with DISCUSSION areas of marginal invasion of the capsule (Figure 5) and micro angioinvasion of the capsule (Figure 6). The pathology The detection of a pyramidal lobe or a thyroglossal duct in patients with hyperthyroidism is indicative of autoimmune

hyperthyroidism. The vestiges of thyroglossal tract are more Malignant tumors arising from thyroglossal duct are also often seen in patients with Graves Disease compared with rare [18]. The majority are papillary carcinomas (about 94%) patients with autonomously functioning thyroid nodules and and less than 5% are squamous carcinoma [19]. The Sistrunk this is related with the presence of stimulating thyrotropin procedure that implies the simultaneous removal of the receptor antibodies [6, 7]. Pyramidal lobe can be the primary central portion of the hyoid bone to ensure the complete or secondary site of thyroid malignancy and during removal of the thyroglossal tract is enough for thyroglossal thyroidectomy, total excision of the pyramidal lobe is squamous carcinoma although they have a poor prognosis essential for patients with thyroid cancers who undergo and a mortality rate of 30-40% [20]. On the other hand, radioactive iodine treatment (RAI) because the presence of papillary thyroglossal carcinomas are multicentric and pyramidal lobe prevents the increase in TSH and absorbs a multifocal and total thyroidectomy followed by 131I ablation large amount of the isotope and thus decrease the possibility and thyroid-stimulating hormone suppression is often to benefit from the treatment [8-10]. Residual pyramidal required. There are still controversy regarding the need for lobe can harbor cancer cells and from this point of view its total thyroidectomy, central or lateral compartment neck total excision is indicated in thyroid cancers. In case of dissection and I131 ablation therapy in cases of papillary probable recurrence of malignant diseases due to pyramidal carcinoma of thyroglossal duct [21]. The decision depends remnants, scintigraphy, ultrasound of the neck, computed on: tumor size (tumors larger than 1 cm require total tomography are indicated [11-13] thyroidectomy), abnormal findings of thyroid (multinodular goiter, cold nodule in a thyroid iodine uptake), histopa- Thyroid pyramidal lobe can be the origin or recurrent site of thological findings, and the presence of enlarged lymph papillary thyroid carcinoma. Malignant tumors arising from nodes or a history of neck irradiation [22]. pyramidal lobe are rare and are associated with a high rate of concurrent thyroid cancer and it must be differentiated In conclusion: in this report we have described a papillary from thyroglossal papillary cancers because pyramidal thyroid carcinoma arising from a multilobulated pyramidal cancer requires orthostatic thyroid surgery which is not lobe including from a nodular peri-isthmic remnant of the always necessary in papillary thyroglossal cancers [14, 15]. pyramidal lobe (secondary to incompletely resected anterior Pyramidal lobe tumors are associated with poor prognostic tumor of the isthmus), in a patient with Graves Disease. The factors such as: extra thyroidal extension, advanced T-stage, rest of the thyroid parenchyma is non tumoral. The complete cervical lymph node metastasis, advanced AJCC stage (III, IV), resection of the thyroid is necessary because of tumor BRAF mutation, multifocal thyroid cancer [16, 17]. In our aggressiveness and the necessity of radioiodine ablation patient there was one single embedded thyroid focus, no therapy. local lymph nodes metastasis and no distant metastasis. BRAF mutation was negative.

References:

1. Braun, E.M., et al., The pyramidal lobe: clinical anatomy and its patient with Graves' disease remain euthyroid/mildly hyperthyroid importance in thyroid surgery. Surg Radiol Anat, 2007. 29(1): p. 21- following total thyroidectomy--the role of thyrotropin receptor 27. antibodies (TRAb) and vestigial remnants of the thyroglossal tract. 2. Allard, R.H., The thyroglossal cyst. Head Neck Surg, 1982. 5(2): Acta Clin Croat, 2008. 47(3): p. 171-174. p. 134-146. 8. Attie, J.N., et al., Feasibility of total thyroidectomy in the 3. Geraci, G., et al., The importance of pyramidal lobe in thyroid treatment of thyroid carcinoma: postoperative radioactive iodine surgery. G Chir, 2008. 29(11-12): p. 479-482. evaluation of 140 cases. Am J Surg, 1979. 138(4): p. 555-560. 4. Ellis, P.D. and A.W. van Nostrand, The applied anatomy of 9. Zeuren, R., et al., RAI thyroid bed uptake after total thyroglossal tract remnants. Laryngoscope, 1977. 87(5 Pt 1): p. 765- thyroidectomy: A novel SPECT-CT anatomic classification system. 770. Laryngoscope, 2015. 125(10): p. 2417-2424. 5. Heshmati, H.M., et al., Thyroglossal duct carcinoma: report of 10. Pacini, F., et al., Post-surgical use of radioiodine (131I) in 12 cases. Mayo Clin Proc, 1997. 72(4): p. 315-319. patients with papillary and follicular thyroid cancer and the issue of remnant ablation: a consensus report. Eur J Endocrinol, 2005. 6. Kallee, R.W.U.M.E., Hyperthyroidism with or without pyramidal 153(5): p. 651-659. lobe: Graves‘ disease or Disseminated Autonomously Functioning Thyroid Tissue? Clinical Nuclear Medicine, 1997. 22(7): p. 451-458. 11. Ryu, J.H., D.W. Kim, and T. Kang, Pre-operative detection of thyroid pyramidal lobes by ultrasound and computed tomography. 7. Cigrovski-Berkovic, M., D. Solter, and M. Solter, Why does the Ultrasound Med Biol, 2014. 40(7): p. 1442-1446.

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12. Cengiz, A., H. Saki, and Y. Yurekli, Scintigraphic evaluation of remnant pyramidal lobe. ANZ J Surg, 2011. 81(4): p. 304. thyroid pyramidal lobe. Mol Imaging Radionucl Ther, 2013. 22(2): p. 18. Weiss, S.D. and C.C. Orlich, Primary papillary carcinoma of a 32-35. thyroglossal duct cyst: report of a case and literature review. Br J 13. Zivic, R., et al., Surgical anatomy of the pyramidal lobe and its Surg, 1991. 78(1): p. 87-89. significance in thyroid surgery. S Afr J Surg, 2011. 49(3): p. 110, 112, 19. Wexler, M.J., Surgical management of thyroglossal duct 114 passim. carcinoma: is an aggressive approach justified? Can J Surg, 1996. 14. Machens, A., H.J. Holzhausen, and H. Dralle, The prognostic 39(4): p. 263-264. value of primary tumor size in papillary and follicular thyroid 20. Boswell, W.C., et al., Thyroglossal duct carcinoma. Am Surg, carcinoma. Cancer, 2005. 103(11): p. 2269-2273. 1994. 60(9): p. 650-655. 15. Witt, R.L., Initial surgical management of thyroid cancer. Surg 21. Dedivitis, R.A. and A.V. Guimaraes, Papillary thyroid carcinoma Oncol Clin N Am, 2008. 17(1): p. 71-91, viii. in thyroglossal duct cyst. Int Surg, 2000. 85(3): p. 198-201. 16. Ogawa, C., et al., Follicular carcinoma arising from the pyramidal 22. Kazemi, M., et al., Primary papillary carcinoma in a thyroglossal lobe of the thyroid. J Nippon Med Sch, 2009. 76(3): p. 169-172. duct cyst. Hell J Nucl Med, 2006. 9(1): p. 39-40. 17. Lee, Y.S., et al., Recurrence of papillary thyroid carcinoma in a

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 now, approximately 250 cases have been published but we still don’t understand the etiopathogeny of the disease. It is Cogan syndrome is a disorder characterized by the considered an autoimmune disorder. This disease seems to association between the Meniere-like vestibulo-auditory affect young Caucasian adults with ages ranging between 25 symptoms and ocular symptoms (interstitial keratitis). to 35 years old, in most of the cases. [5] Although the first to describe a disorder associating ocular and inner ear symptoms were Morgan RF, Baumgartner in CLINICAL FEATURES 1934 [1], the name of the disease comes from Dr. David Cogan who published in 1945 a series of 4 cases of patients Ocular manifestations: The main characteristic of the with non syphilitic interstitial keratitis and vestibulo- disease is the ocular involvement. Usually patients have red auditory symptoms [2]. In 1980 Haynes et al proposed the eye, eye pain and photophobia. The typical Cogan syndrome enlargement of the criteria for the diagnosis, defining typical is defined by the presence of the non syphilitic interstitial and atypical Cogan syndrome. They proposed that other keratitis. The examiner might notice granular and irregular ophthalmologic inflammatory manifestations such as infiltrate on the posterior part of the cornea. episcleritis, uveitis, conjunctivitis, can be considered as Neovascularization is also a possibility. Blindness and disease criteria for atypical syndrome. [3] amaurisis can happen but usually the lesion regresses and the loss of visual acuity is moderate. In the majority of the For a disease described such a long time ago there is very cases both eyes are affected, the unilateral disease is little knowledge about the etiology of the disorder. Until infrequent [6]. In the atypical Cogan syndrome the vestibulo- cochlear manifestations can be associated with scleritis, episceritis, uveitis, optic neuritis, conjunctivitis or glaucoma. 1 St Maria General Hospital, Bucharest, Romania 2 Carol Davila University of Medicine and Pharmacy, Bucharest, [7] Romania 3 Carol Davila University Emergency Central Military Hospital, Vestibulo-cochlear symptoms: Cogan syndrome is classically Bucharest, Romania characterized by sensory-neural hearing loss, vertigo and

66 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine tinnitus in an association that resembles to Meniere’s Differential diagnosis disease. The hearing loss might be profound, leading to The first differential diagnosis one should bear in mind when cophosis in almost 52% of cases and usually it is bilateral. The facing a rapid onset hearing loss with vestibular symptoms auditory deficit is installed in days, months, too slow for a and interstitial keratitis is syphilis. Another important sudden nerosensorial hearing loss and too quick for a differential diagnosis is Meniere’s disease but in this case the presbyacusys. The speech discrimination scores are poor. ocular manifestations are absent. The hearing loss is associated with tinnitus. [4] Another diagnosis to be differentiated from Cogan is Susac The vertigo can be important causing marked instability, syndrome, a retino-cochleo-cerebral vasculopathy involving ataxia, sometimes associated with nausea and vomiting. The the arterioles, manifested by central neurological disorders, nystagmus can be observed at the ocular examination. In visual acuity loss, and hearing loss.[10] Vogt- Koyanagi- most of the cases, complains are similar to Meniere’s Harada syndrome is characterized by uveitis, alopecia, disease. vitiligo and audio-vestibular symptoms.[11] . Other systemic Other signs and symptoms diseases such as Wegener granulomatosis, PAN, relapsing polychondritis, Behcet disease, and Sjogren syndrome can General manifestations of the disease are not rare, fever has associate vestibulo-auditory symptoms with ocular been reported in many cases, weight loss and extreme involvement. asthenia can be found in patients with Cogan’s. Evolution, prognosis Cardiac involvement, especially aortic insufficiency is present in as much as 15% of cases. Large vessels can also be In some cases, the onset of the disease is preceded by upper affected causing heart murmur, abdominal pain, respiratory tract viral infection. claudication of the members. The vestibular and auditory symptoms can be the first Musculo-scheletal involvement manifests as myalgia or manifestations of the disease in 41% of cases. in 43 % of arthritis (mono, oligo or polyarthritis). cases the Cogan syndrome debuts with the ocular symptoms. The involvement of the two organs is usually Neurological signs appear in ¼ of cases [8], patients might done in approximately 3 months [8]. In cases of atypical have paresis, hemiplegia, aphasia, cerebellar syndrome, Cogan syndrome the complete symptomatology might be pyramidal syndrome, spinal cord disorders, epilepsy, and installed in a long period, even years. vigilance disorders. MRI can sometimes detect lesions of the white matter consistent with cerebral vasculitis. Usually, after the first attack the disease enters a phase of remission without evident symptomatology. There is a Cutaneous lesions might appear during attacks taking the possibility that there are recurrent episodes that repeat at form of urticarial rash, vascular purpura, ulcerations or variable intervals. Once installed the hearing loss is not nodules. remissible. The vestibular symptoms diminish as a result of Some patients might have gastro-intestinal or pulmonary the compensation mechanisms. The ocular symptoms have symptoms. a variable evolution, but usually respond favorably to treatment. Laboratory investigations Treatment Biologic parameters can be modified in Cogan syndrome, especially during the attacks, but no laboratory test in As the etiology and the pathogenic mechanisms are not pathognomonic for the disease. Leukocytosis, elevated ESR, known, there is not yet available a codified treatment for anemia, hyperfibrinemia may appear. Several immune- Cogan’s syndrome. logical modifications also can be noticed: rheumatoid factor, Usually the first line of treatment is represented by antinuclear antibodies, cryoglobulins, lupus anticoagulant corticosteroids. [12] In cases where the corticodependence but none of these are specific or relevant for the disease. [9] is installed or in cases of corticoresistance there is the In small series of patients, some authors determined the possibility of using other therapeutic agents such as presence of specific antibodies for the inner ear or cornea immunosupressants (cyclophosphamide, azathioprine, and but these studies were not relevant and could not be methotrexate). [13] The corticotherapy should be prescribed reproduced by other authors so cannot be used to support in high dosage (1-1.5 mg prednisone or equivalent) and the diagnosis of Cogan. interrupted in two weeks in cases where it is ineffective. Studies show that the vestibulo-cochlear symptoms respond

to treatment only in one third of the cases (orphanet). Once data, the ENT exam was within normal limits. the deafness is installed, it is usually non-reversible. The vestibular examination pointed out to an important In the last years there were attempts to treat Cogan instability, the patient was unable to maintain orthostatic syndrome with TNF alfa blockers but there are not enough position or walk without support, no spontaneous evidence based results [14, 15] nystagmus.

The cerebral IRM examination did not reveal any vascular or CASE REPORT tumoral lesions. The neurologic examination did not We present the case of a 40 years old woman with no discover any motor or sensorial deficit, no signs of remarkable medical history who presented at the localization. emergency department of our hospital accusing sudden The audiogram performed initially can be visualized in Figure onset intense vertigo and dizziness, tinnitus and hearing loss 1. We diagnosed a profound sensoryneural hearing loss for in the right ear. The patient was admitted in the ENT the right ear and a medium sensory-neural hearing loss for department. the left ear. The physical examination of the patient yielded no relevant

Figure 1: Initial audiogram

The rheumatologic examination revealed no remarkable (Figure 2). findings: no arthritis, no cutaneous lesions, and no ocular The videonystagmography with caloric testing evidenced a symptoms. total right areflexia and an extremely important left The blood hematological and biochemical parameters were hyporeflexia (Figure 3). modified showing a slight leukocytosis with a white blood We started a treatment with high dose corticotherapy (solu- count of 11000/mm3, the ESR also slightly elevated 25 medrol), antiemetic (osetron), vestibular suppressant mm/hour and the CRP had the value of 5. The modifications (diazepam), vasoactive agent (pentoxyphilin), vitamin (B1 were interpreted as a reaction to an acute dental infection and B6), plasma expander(dextran 40). the patient had at that moment. During the treatment, the patient presented a fluctuating All the immunologic tests we performed were in normal evolution. The hearing level fluctuated especially on the left limits, IgA, IgG, IgM, ANA, antibodies anti beta 2 ear with PTA between 30 and 60 and on the right ear with glycoprotein, antibodies antiphospholipid were tested and PTA between 60 to 90. the values were normal. Antibodies Ig M and Ig G for Epstein Bar virus, Toxoplasma, HIV, herpes virus, cytomegalovirus In Figure 4 it can be noticed the aspect of two audiograms were all negative. we performed during the treatment in which we could observe the fluctuant hypoaccusis in both ears. The ophthalmologic examination did not find any modifications of the anterior ocular pole at that initial The dizziness also fluctuated with episodes of severe vertigo. moment. In these episodes, the direction of the nystagmus varied. We recorded horizontal rotatory nystagmus beating to the left The computerized posturography we performed at but also to the right (Figure 5) alternating with periods of lack admission showed a severe vestibular deficiency pattern

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

Figure 2: Computerized posturography

Figure 3: Videonystagmography

Figure 4: Audiograms during the treatment

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 again at the emergency department accusing intense discharged with an improvement of the hearing loss in the vertigo, nausea, vomiting, tinnitus and aural fullness in the left ear, no vertigo and only a mild dizziness. left ear. The audiogram evidenced a bilateral severe hearing loss (Figure 6). One month after this episode, the patient presented once

Figure 6: Bilateral severe hearing loss

The rheumatologic examination did not reveal any The patient was discharged with a prescription of modifications. The second day of hospitalization the patient prednisone in low dose for a period of three months. suddenly presented eye pain with intense redness of the One year later, in the follow up, we noticed that the hearing conjunctive. The ophthalmologic examination established in the right ear did not improve at all but the instability the diagnosis of kerato-conjunctivitis (Figure 7). improved a lot so the patient was able to continue with In this moment, we were able to diagnose an atypical Cogan everyday life. In this year she did not have any attack, no syndrome taking into account the association between the audiovestibular or ocular symptoms. audio-vestibular symptoms with an inflammatory ocular DISCUSSION disease. Haynes et al described atypical Cogan syndrome for the first We repeated the same treatment as in the first episode time in 1980. The typical Cogan syndrome was described as associating local eye topical corticosteroids and artificial tear an association between Meniere–like audio-vestibulary solution with a major improvement of the hearing loss for symptoms and non-syphilitic interstitial keratitis with an the left ear PTA 10 (Figure 8).

70 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine interval between the onsets of the symptoms of less than ocular and audio-vestibular manifestations. two years. The atypical Cogan syndrome with ocular manifestations other than interstitial keratitis tends to have a higher rate of Figure 7: Kerato-conjunctivitis 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 The atypical Cogan syndrome consists in an association of treatment was similar. During the admission we performed symptoms in which the disease criteria are grouped as multiple audiograms evidencing the fact that the thresholds follows: at both ears were in a continuous modification, not • Inflammatory ocular manifestations with or without respecting the classical pattern of Meniere’s. The interstitial keratitis videonystagmography with calorics showing bilateral • Typical ocular manifestations associated with audio- vestibular lesion from the beginning of the disease, was also vestibular symptoms different from Meniere’s atypical for Meniere. • A delay of more than 2 years between the onset of typical

Figure 8: Major improvement of the hearing loss for the left ear

The onset and evolution of the disease made us believe that this patient. Another remark is the fact that the patient is there is a autoimmune disorder of the inner ear but we did over the age of typical onset of the disease, but there are not have any disease criteria to classify. The laboratory tests many reports of atypical Cogan with patients in the same age were within normal limits, the minor leukocytosis and the group. [17, 18] slight elevated ESR were not noticeable. No other The response to corticotherapy, was partial as the right ear immunologic tests were modified or virus infections did not recover, but the final result was considered detected. satisfactory by the patient who could continue her daily At the second episode of disease, the concomitance with the activities. 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

CONCLUSION Typical and atypical Cogan syndrome are diagnosed mainly based on clinical criteria as there are no laboratory tests able Although Cogan syndrome is a rare disease, we must bear in to evidentiate the disease. mind that there is always a possibility of diagnosing it in the case of a patient with both vestibule-auditory symptoms and The treatment consists mainly in corticotherapy. Immuno- ocular manifestations. suppressants are an option in cases where corticotherapy is inefficient.

References:

1. Morgan RF, Baumgartner CJ. Ménière’s disease complicated by 10. Kleffner I, Dörr J, Ringelstein M for the European Susac recurrent interstitial keratitis: excellent result following cervical Consortium (EuSaC), et al Diagnostic criteria for Susac syndromeJ ganglionectomy. West J Surg 1934;42:628-31. Neurol Neurosurg Psychiatry;87:1287-129. 2016 2. Cogan DG. Syndrome of nonsyphilitic interstitial keratitis and 11. Andreoli CM, Foster CS. Vogt-Koyanagi-Harada disease. Int vestibule-auditory symptoms. Arch Ophthalmol 1945;33:144-9. Ophthalmol Clin. Spring. 46(2):111-22. 2006 3. Haynes BF, Kaiser-Kupfer MI, mason P, Fauci AS. Cogan 12. E. W. St. Clair and R. M. McCallum, “Cogan's syndrome,” Current syndrome studies in thirteen patients, long term follow-up, and Opinion in Rheumatology, vol. 11, no. 1, pp. 47–52, 1999 review of the literature Medicine.1980 69426-41 13. L. Riente, E. Taglione, and S. Berrettini, “Efficacy of 4. M. B. Gluth, K. H. Baratz, E. L. Matteson, and C. L. W. Driscoll, methotrexate in Cogan's syndrome,” Journal of Rheumatology, vol. “Cogan syndrome: a retrospective review of 60 patients throughout 23, no. 10, pp. 1830–1831, 1996 a half century,” Mayo Clinic Proceedings, vol. 81, no. 4, pp. 483–488, 14. Z. Touma, R. Nawwar, U. Hadi, M. Hourani, and T. Arayssi, “The 2006 use of TNF-α blockers in Cogan's syndrome,” Rheumatology 5. J. Cundiff, S. Kansal, A. Kumar, D. A. Goldstein, and H. H. Tessler, International, vol. 27, no. 10, pp. 995–996, 2007. “Cogan's syndrome: a cause of progressive hearing deafness,” The 15. M. Fricker, A. Baumann, F. Wermelinger, P. M. Villiger, and A. American Journal of Otolaryngology, vol. 27, no. 1, pp. 68–70, 2006 Helbling, “A novel therapeutic option in Cogan diseases? TNF-α 6. R. M. McCallum and B. F. Haynes, “Cogan's syndrome,” in Ocular blockers,” Rheumatology International, vol. 27, no. 5, pp. 493–495, Infection & Immunity, J. S. Pepose, G. N. Holland, and K. R. 2007. Wilhelmus, Eds., p. 446, Mosby, St. Louis, Miss, USA, 1st edition, 16. João Queirós, Sofia Maia, Mariana Seca, António Friande, Maria 1996 Araújo, and Angelina Meireles, “Atypical Cogan's Syndrome,” Case 7. A. Grasland, J. Pouchot, E. Hachulla, O. Bletry, T. Papo, and P. Reports in Ophthalmological Medicine” 2013 Vinceneux, “Typical and atypical Cogan’s syndrome: 32 cases and 17. Cogan's syndrome--an interdisciplinary diagnostic challenge. review of literature,” Rheumatology, vol. 43, pp. 1007–1015, 2004 Lyhne NM, Mortensen MV. Ugeskr Laeger. 173(40):2503-4) 2011 8. P. Vinceneux, Cogan Syndrome, Orphanet Encyclopedia, 2005 18. Ying YL, Hirsch BE. Atypical Cogan's syndrome: a case report. Am 9. R. S. Vollertsen, T. J. McDonald, B. R. Younge et al., “Cogan's JOtolaryngol. Jul-Aug;31(4):279-82. 2010 syndrome: 18 cases and a review of the literature,” Mayo Clinic Proceedings, vol. 61, no. 5, pp. 344–361, 1986.

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Article received on May 3, 2019 and accepted for publishing on June 30, 2019. 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 health expectations are not in vain. Moreover, it is very consider the patient an active factor in his own healing important to pay a close attention to communicating with process. Placement of the patient in the center of healthcare him; it is even said that this type of communication is the services aims at his loyalty, which means creating and broker of the relationship developed in a sensitive and maintaining correct and long-lasting relationships with him. dynamic environment like the healthcare field. In addition, in order to create such relationships with The complexity of providing healthcare services, on the one patients, both loyalty and stability, performance, and hand, and the wishes and expectations of patients, on the profitability strategies of the medical team must be thought other hand, have as result special patient-physician on long-term. communication valences and turn it into an essential Healthcare marketing situations differ, and medical units condition. Permanent and effective communication with concerned with the essence of success must strive for a patients has become a condition of the existence of a strategic alignment of relationships between all qualitative medical act. stakeholders (decision-makers, medical staff, patients, etc.) Given the continuous increase and diversification of health and the power of these relationships to improve their services, communication issues are becoming increasingly mutual value and even the relational context as a whole, difficult and require much more laborious information turning patients into true brand promoters, thus enhancing efforts. marketing efforts [1]. Due to the information explosion, patients tend to The patient reaches to attitudes, judgements, and appreciate the quality of a product or service based on preferences about certain brands through a procedure of perceptions rather than on reality. evaluating the features of these brands, developing a set of beliefs about the features that correspond to each brand [2]. That is why efforts to optimize the technological and informational processes of communication between Recognition of the strategic relationship that a patient patients and medical staff, of exploring patients’ behaviors desires is a medical marketing reality and involves greater regarding interpersonal communication in electronic commitment to accepting the challenge of creative thinking environments in health services, of modeling negative in often difficult situations, progressing through knowledge emotions, of ways of transforming the healthcare and understanding to mutual trust, converting emotions into infrastructure so that it offers an integrated insight of balanced normality and the relationship thus created into an information through the optimized clinical and business emotional-connected and loyal one for a certain period of processes, of welfare and health management, of patient- time. This means concentrating efforts on patients, centered networks, of investigating the influence of virtual attention, and receptiveness to his wishes, but communities on the reputations of health organizations in professionalism and rigor in such a way that his personal Romania, has become a permanent necessity [3].

The relationship between the two sides, medical staff- being forced to seek support whenever he needs. Thus, the patient, in the healthcare field, is much more complex, patient is the most disadvantaged person, being influenced addressing social, psychological, and cultural aspects, which by physical and mental suffering, feeling the disease as a besides the base of the therapeutic level also implies a source of uncertainty and insecurity, while the physician is superior level of existential communication. The latter is regarded as a person with multiple qualities, full of energy found in medical communication because the medical act and sometimes with magical powers. interferes with the destiny of the patient, linked in turn with Gaining a high communicative competency needed by the elements of uncertainty and individual instability [4]. specialist to create a real therapeutic alliance requires not Interpersonal communication was the first spiritual only solid medical knowledge to diagnose and treat the instrument of the human being in the process of socializing, disease but also the ability to obtain as much information as and is defined as the communication that occurs between possible from the patient and interpersonal skills to respond two people in the context of their relationship and which, as to feelings and patient concerns and the ability to create and it evolves, helps them negotiate and define the relationship maintain the therapeutic relationship as a concrete offer of [5]. information and medical education [7].

Communication within the health organization takes place in Health communication is “the study and use of a complex environment, where continuously modifying communication strategies to inform and influence the favorable and unfavorable factors coexist. Communication choices people make regarding their health”, and health can take many forms and can be seen in different situations, information technology includes “digital instruments and but the most important of these is undoubtedly between services used to enhance self-care of patients, assisting patient and physician, which provide much of the data patient-provider communication, informing about health needed to establish the diagnosis and therapeutic attitude. behaviors, preventing health complications and promoting equity in health” [8]. Interpersonal communication is formed by the combination of verbal forms (oral and written), nonverbal forms A major concern of health services and primarily of hospitals (gestures, mimics, posture, movement, aspect) and has become communicating with patients, the quality of paraverbal forms (by voice attributes accompanying the information provided to patients by physicians and the rest word, such as intonation, rhythm, verbal flow), but, of the medical team. An essential component is the considering the importance of the information content of transmission of information, which has become increasingly patient-physician communication (the diagnosis and important in medical deontology. This development is treatment process), in the medical system, the emphasis is primarily driven by wishes of patients, more trained in health more on verbal communication. Non-verbal and paraverbal issues, and more cautious about the quality of the forms are important from the point of view of their explanations they are given. emotional effect and the formation of sympathy. In the hospital environment, where the patient is subject to In the health system, the relationship between the two sides, the attention of medical teams, the coherence of “what is the medical staff-patient, is much more complex, involving a said and what is not” becomes a permanent goal for patients higher-level therapeutic type of existential communication. and their relatives. Because, beyond anything “...there is an This type of communication [4] is involved in medical informational asymmetry between the physician and the communication, because the medical act interferes with the patient: when they find themselves in the hospital (...), they destiny and evolution of the patient, being in turn linked to feel ill, they do not feel what is going on with them, they do elements of uncertainty and individual instability. not know the possibilities of medical science, so they empower the physician with the freedom of choice” [9]. A On the other hand, the position of the two entities, namely good professional behavior is to state exactly how we are the medical staff-patient, is different and unequal [6]. This feeling and to write what we are saying. However, each relationship is established between members of two distinct physician is the supreme judge of how he or she does and social groups in terms of their prestige, power, and can enrich his or her oral information by using information orientations. Thus, the physician has an extremely high charts and, if considered necessary, by other documents or status, given the level of information held and the video support. specialized guidance through which he exercises his full authority. In healthcare services, access to online information has made patients more aware of their needs and desires so the The social role of the patient demonstrates his vulnerability, result has materialized in a rigorous selection of service

74 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine providers. service requested. Similarly, the attitudes and behavior of healthcare participants will influence the perceptions of Therefore, healthcare managers and providers need to current performance. Contextual elements can also understand the stages a potential patient is going through in influence satisfaction in the confrontation with the medical an online buying process or when expressing an intention to service, through their effects on attributions (of causes) for buy an online health product or service. invalidation. Theory of attribution asserts that when results The winners will be those who build trust from the patient’s are not in line with expectations, people tend to look for perspective, with three progressive complex components in reasons. The importance they give to “why”, will influence the relationship between the brand and him: credibility, the final evaluation of the outcome. care, and congruence. Certainly, what is very important is The communication process is very important within the the amount of money spent by the patient for the recovery medical unit; it is a process that affects the quality of the of health. other processes. Through the positive impact on Nowadays, in health systems, the widened marketing mix communication within the medical unit, the style oriented enjoys considerable attention. It provides a simple towards maintaining socio-emotional aspects and the organizational mechanism to understand the problems leadership style oriented towards relationships is beneficial arising from the concerns of medical service providers. The to the processes within the medical unit and to the widened mix has also developed as a partial solution to some emergence of positive socio-emotional states. This of the most important problems faced by managers in terms leadership style is associated with the existence of high of quality control of healthcare services provided and the quality communication relationships, which leads to the relationship with patients in the process of providing these improvement of the quality of the other processes [10]. services. The widened mix explicitly recognizes the role of In the new context of health, development processes will the staff and patients in the service delivery process, need to focus not only on solving current problems, but also highlighting the role of marketing played by both sides. on anticipating future problems, not just on certain types of The inclusion of Physical Evidence, Participants, and Process processes, but as many as possible, not just on technical as distinct (contextual) elements underlines their resources, but more on human ones. Organizational- importance and impact on marketing of health services. In managerial excellence seeks not just the adaptation to addition, the key objectives are to increase patient circumstances, but also the becoming and the power to satisfaction, quality of medical services offered and long- create the circumstances [11]. term patient gaining, which means that the widened The depth of the process of change in health, its size, and its marketing mix management is directly related to these dynamics depend not only on the political will and on the objectives. subjective aspirations, but also on the existence and Due to the immaterial nature of healthcare service and the sufficiency of the necessary objective conditions, the fact that, usually, they cannot be checked beforehand, managerial ones being the first. patients are looking for tangible evidence of what they are In the context of today’s healthcare problems, the special about to experience in a particular immediate confrontation role of the manager is imposed by the need to create a with the medical service. Even if a patient has a high general capacity for innovation, flexibility, stability, and experience with such a healthcare provider, variations, and ensuring success even in extreme situations. In this context, contextual elements will affect patient’s expectations the theoretical but especially the methodological approach related to the immediate confrontation with a medical of the marketing of the medical system has special practical service. valences, requiring a change in the mental attitude of health Elements of “Physical Evidence”, such as noise level, smell, managers towards an innovative strategic hospital temperature, time, comfort, and even nutrition, will marketing oriented towards and for the benefit of patients influence the perceptions of confronting with the healthcare [12].

References:

1. Batterley R. Leading Through Relationship Marketing. 2004, 2. Kotler P, Shalowitz J, Stevens RJ. Strategic marketing for Health McGraw-Hill Australia Pty Ltd. Care Organizations - Building a Customer – Driven Health System. 2008, Jossey Bass A Wiley Imprint.

3. Purcarea VL. Impactul tehnologiilor informationale asupra 8. https://www.healthypeople.gov/2020/topics-objectives/ sistemului de sanatate. Teza de abilitare, 2013. topic/health-communication-and-health-information-technology. 4. Cosman D. Psihologie medicală. 2010, Iaşi, Editura Polirom. 9. de Kervasdoné J. La generalité de soin on France. 2000, 46. 5. Floyd K. Comunicarea interpersonală. 2013, Iaşi, Editura 10. Curşeu PL, Schalk MJD, Wessel I. How do virtual teams process Polirom. information?. A literature review and implications for management. 6. Chichirez CM, Purcărea VL. Interpersonal Communication in Journal of Managerial Psychology. 2008; 23,6,628-652. Healthcare. Journal of Medicine and Life. April-June 2018; 11. Ciurea AV, Ciubotaru VG, Avram E. Dezvoltarea 11(2):119-122. managementului în organizaţiile sănătăţii. Excelenţa în serviciile de 7. Servellen van GM. Communication skills for the health care neurochirurgie. 2007, Bucureşti, Editura Universitară. professional: Concepts, practice, and evidence. 2009, Canada, Jones 12. Popa F, Purcarea Th, Purcarea VL, Ratiu M. Marketingul & Barrlett Publishers. serviciilor de ingrijire a sanatatii. 2007, Bucuresti, Ed. Universitara ”Carol Davila”.

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Article received on May 12, 2019 and accepted for publishing on June 30, 2019. VARIA

The tree we throw stones at

Mihail Mihailide

I stop to catch my breath on the crest of a hill in Predeluţ. 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 It's late autumn with a blue-diamond sky. Nevertheless, eternal sleep anywhere else. "Today, a commemorative there is fresh snow fallen on the rugged tops of the plaque and the name of a street in Bran remind us of this son mountains and on the hedges of dark fir trees at the foot of of the region”, noted Emil Stoian, the brave chronicler of this the Bucegi mountains – looking as if they were mounted beautiful mountain village, to whom the inhabitants owe a lancers. The snow is glistening. major contribution for preserving the image of those who I feel the tall grass, dried by the season, under my feet. On really meant something for the Romanian people. Such the twisted and black branches of the old apple trees, red people are numerous, in Bran: historians, philologists, fruit swing in the scented wind. Around the roots of the lawyers, physicians, actors, officers, priests, professors and some apple trees – there are spots of royal purple perennial academicians; participants in the Great Union of 1918; irises. Although poisonous flowers, I can’t resist their calling heroes of the two World Wars. I have met some of the beauty and I lift a few threads. physicians… 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

Found at the location, I feel disappointed: where is the and modern digitization was stopped for various reasons... tomb? I am told to go two kilometers uphill on the right side Iancu Gonţea was one of my professors in my fourth year at of the road. This time I decide to walk. Indeed, after passing the Bucharest Faculty of General Medicine. Decades have the Primary School, on the yellowish wall of which a thin gone by. Before proceeding to "serious things", I ask the marble plaque reminds that the scholar attended his first reader's permission to reproduce a few paragraphs, surely classes "here", I pass by the house and the yard where he forgotten by the reader, perhaps funny, from the notes was born and spent his childhood, its gate always locked, and about the professor of the Food Hygiene Department, who arrive at the church dedicated to St. Nicholas, standing a few was born in Şimon and returned there at the end of his life. 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.

"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 From an oval photograph, embedded in the austere concrete Gonţea himself. At the end, he wrote down the grade that wall, the professor gives me a harsh look. Where should I put each of us deserved in our grade-books and we tiptoed out the irises brought as a modest homage? It's difficult to find of the lab. In the hall, we were approached by our classmates your way between the graves... who, browsing through their notebooks, were trying to learn everything they hadn’t learnt until then, before entering the I have synthesized ergo-biographical data regarding Prof. lab room „to have their heads cut off". Iancu Gonţea in a book [2], using sources coming mainly from the archives of the medical-historical documentation – What subject did you pick? Does he also ask questions from library of the National Public Health Institute of Bucharest, «the practical experiments»? Is he harsh, is he kind? What an institution whose enrichment with new information grade did you get? Many of the questions were difficult to (manuscripts, photos, video tapes, books, magazines, etc.) answer promptly... At a certain moment, one of the best

78 Vol. CXXII • No. 2/2019 • August • Romanian Journal of Military Medicine students of our class came out of the lab, almost bursting occupational and environmental conditions, «for the first into tears, obviously confused. time demonstrating that physical activity increases protein and calcium needs, as well as vitamin C consumption, [and – What happened? What subject did you get? that] exposure to chemical noxae heightens the metabolism – The third question, she explained us, as she started to feel of thioamide acids and of ascorbic acid, increasing the needs better, was about the trophic content of the main foods. I of the body.» explained how many proteins, lipids, fats and calories can be In the same CV requested by the Academy of Medical found in cow's milk, eggs, fish, chicken and I don’t know what Sciences, the professor listed the procedures he had devised else I mentioned... I couldn’t realize whether he was satisfied for the biochemical control of vitamin nutrition status, as or whether I had gotten it all wrong. I finished what I had to well as the methodology for studying the biological value of say, but then he asked me additional questions, looking at food, both highly appreciated by international scientific me over his glasses: bodies. – «What about ordinary vegetables, which of them have a The professor was to be awarded an important international higher vitamin content?» I gave the wrong answers, I prize (Maurel) as well as the silver medal in food science for stammered and then I said: carrots, spinach, tomatoes... his contribution regarding natural anti-nutritional Whatever! substances in food and animal feed. I. Gonţea also – «What a-bout-par-sley?» he asked. I was as quiet as a fish. demonstrated that no food is complete and set up an Total silence. He gave me the right answer and explained original classification of foods (by groups), embraced by why his question was so important. Then he added: experts of his time, in keeping with the benefits and the deficiencies of various food categories."[5] – «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 Given their originality and practical value, based on rigorous qualities of this ancient vegetable: «It also ensures the good laboratory and field research, many of his writings have been functioning of the genitals and even has a powerful translated into widely-circulated foreign languages. They aphrodisiac effect! »”[3] cover the fields of effort physiology, pathophysiology, and Writing about himself in a curriculum vitae requested by the medical clinic, but most of them include research on human Academy of Medical Sciences (AMS), whose member he nutritional needs under different physiological, occupational became, professor Iancu Gonţea believed that he had set a and environmental conditions: "Food Control" (1956), "Food "new trend in the science he practiced, which was seen not Ration" (1956), "Rational Nutrition of Women during only as food hygiene, studied separately from the man (in a Maternity and Its Importance for Mother and Child Health" narrow technical-sanitary concept), but as the science of (1958) can be considered as major landmarks in medical biomedical, psycho-social, and economic relations between literature, at least in the Romanian one. The last of the books man and food"[4]. He has the merit of having contributed to mentioned were updated by the author, translated into determining the nutritional requirements in relation to one's German, and published by the prestigious publishing house

Gustav Fischer of Jena in 1965. Having received excellent "Sanitary Merit”, alongside other scientists rewarded "for reviews, this monograph was requested, from the German the contribution to the Party's policy in the field of public publishing house, by Dai-lichi Co. Ltd. Publishing House in health in our country". The chairman of the Council at the Tokyo and became the first book by a Romanian scientist time was N. Ceauşescu, while the minister of health – Prof. published in Japan, in 1974. 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, In 1963, the Medical Publishing House (Bucharest) released born in the village of Şimon, on February 10, 1907), and "The Bases of Nutrition". Three years later, another book therefore, seeming to be imbued with socialist "principles" was published: "Natural Anti-Nutritional Substances in Food and "ethics" – was to be placed under surveillance by the and Animal Feed" (in association with Paraschiva Şuţescu, Securitate (being the subject of two files, "I. 498910")? [7] Ph.D.), subsequently translated into French and published by He maintained correspondence with scientists from all over Vigot Frères Publishing House, in association with prof. the world; often travelled to Western countries but also to Raymond Ferrando PhD (Paris, 1967), as well as into English, the Soviet Union; he attended medical conferences; worked and published by Karger Publishers in Basel (Switzerland) [6] in the field of food hygiene, this having a great social impact. as well as in New York (1968). The Academy of the Socialist He represented the Socialist Republic of Romania in the Republic of Romania awarded professor Gonţea the "Victor World Health Organization. All this supposed that his loyalty Babeş” prize for this book. Among the books that were to the "party and to the socialist homeland" were to be published, almost every year, two titles still stand out, continuously tested by the "state bodies"... several decades later:" A Genetic Leap in the Nutritional Value of Corn – the Past and Present of this Cereal” (Ceres The "vigilance" of the Securitate also translated into an Publishing House) and "Alcoholism" (Medical Publishing internal decision issued on November 18, 1969, regarding House, 1976), an insight from the point of view of preventive the preservation of his "informative" file in the Operational medicine into the use and over consumption of alcoholic Fund, under no. I. 715753, coming from the 3rd Directorate drinks – "considered to be a serious problem on a national of the feared institution… level". What was pursued Iancu Ion Gonţea accused of?

Professor Iancu Gonţea won high recognition in the scientific That "he was a member of the Iron Guard, working in the events he was invited to — international congresses and Sanitary Department of its Documentary Studies Center." symposiums (Dresden, Moscow, where he accompanied the That, "he was a major in the bourgeois army" (a member of Romanian delegation as an expert in nutritional issues at the contingent of officers who took the military oath before C.A.E.R. meeting, 1969), at New Castle ("Women’s Nutrition the King). Later on that "he maintained correspondence with during the Reproductive Cycle", 1971), Mexico (where he people from abroad, such as Prof. R. Ferrando (France) and presented a paper titled "Nutrition and Anti-Infectious foreign publishing houses." In an informative ("strictly Defense in Humans" ), Austria ("The Effects of Sugar Abuse") secret") note obtained by major I. Ion, at agent "Gabriel" etc. He received national and international awards and home and dated April 17, 1967, he declared that he met the diplomas. person under surveillance during his studies at the Andrei Under a Decree of the State Council of the Socialist Republic Şaguna High School (1924-1927) and added that Iancu of Romania (153/1971), the professor was awarded the Gonţea (I.G.) "was a very good student, who graduated at the top of his class".

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The note provided biographical data, generally consistent exams, asking the students to reproduce all the details, or with that provided by Gonţea in his résumés. I.G. seems to better said the whole lecture, word by word. He does not been the son of poor peasants from Bran; he was not hesitate to turn students out over the slightest mistake. His perform any legionary activities, although his uncle, a history behavior gives the impression of a modest man, deeply teacher, dr. [Ioan] Moşoiu, "who was also the manager of involved in his profession." 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 Elly – a professional informer was a former military physician) and lecturer Coman Petrescu, PhD (a pediatrician dealing with rational child In Iancu Ion Gonţea's file, there is a note received by nutrition). In "Gabriel"’s opinion, allegations that I.G. had captainV. Ovidiu, on April 19, 1957, from agent "Elly", been involved in the legionary movement activities as a reeking of antipathy towards I.G., a text in which one can student were simply "unfounded rumors." hardly tell the truth from "pure" lies. It is difficult, if not downright impossible, to check these allegations because However, in his Note, major I. Ion seemed keen to show his the informer, hiding under the pseudonym given her by the superiors how cautious he was: "Since I.G. is known by the Securitate, seems to be a professional of delation, citing Third Department (of the Securitate) as a former member of people (giving their full names and the position held in the the Iron Guard, the agent will have to inform us of any data Institute) who could allegedly back her allegations, but who backing this assumption. In addition to that, the today, 60 years later, are most certainly dead... correspondence with foreigners will be kept under observation." Next came a list of names – French and "I inform you", wrote Elly, "that Dr. I.G., associate professor German researchers and professors from (Paris) and of nutrition at the Faculty of Medicine, living at 244, (Heidelberg). Dorobanti Street, phone 7.66.29, claims to be «untouchable» because he is backed by Acad. Ștefan Milcu Here is what agent "Titi", who "kept him under observation and Acad. N. Lupu, who are «indebted» to him. during his teaching activities”, wrote: "Always punctual, having a commanding attitude, he teaches the students I.G. is the author of numerous fake public documents and notions of food hygiene during his two-hour lecture. During characterizations (within the IMF – Institute of Medicine and his lectures he seems to speak with passion, having a Pharmacy), helped by former head of the personnel dignified attitude. From talking to other students, the source department At.). All these facts are known by the found out that professor Gonţea is very demanding during management. Dr. I. Per. from the Hygiene Institute, Laboratory of Food Chemistry, 1, Leonte Street, can provide

references in this respect." - The bibliography of the second article includes ten works, all of them English and American. After this "introduction," "Elly" wrote that she knew I.G. since November 1954. "I know that he was a legionary, - This amounts to hostile behavior towards Soviet science, working in the cabinet of another Iron Guard physician, Dr. and within the department, which contrary to the ideological Ru, within the Legionary Ethics Committee – at the time, the orientation of the scientific research in the R.P.R. steering committee of the Faculty of Medicine (?). At that 3) He considers himself a "great patriot and a great time he worked wearing a green, Iron Guard shirt; at Iron Romanian". Under this mask, Assoc. Prof. I.G. hides his Guard rallies he carried banners reading Nu merus nullus ferocious anti-semitism and hatred against elements (sic!) and Nu merus claus (sic!). prof.dr. I.I.N., manager of the dedicated to the working class. References: 1. Gabriela from Institute of Physiology of the R.P.R. Academy, phone 4.20.59 Caritas, phone 2.90.40 who was an assistant at the (home) and Dr. Eug. D.), phone 7.31.16 (home) can give Department of Nutrition, Dr. D. Eugen, phone 7.31.16; M. references about his activity at the time. Among the acts of Maria. St. Constintin Street, No… Petre P. from the Cotroceni hooliganism, I can mention the ones I heard about from Dr. Hygiene Institute. Eug. D., namely that Assoc. Prof. Dr. I.G., under the legionary régime, tried to devastate the Cantacuzino Institute, kicking 4) Assoc. Prof. Gonţea Iancu (hereafter names were blacked the doors when he entered the rooms, destroying laboratory out by the CNSAS) – nurse G. Maria swore to me, in the equipment, etc. In the Military Sanitary Institute where he autumn of 1955, on the health of her child, that, as head of worked for some time, the whole institute knew him as a the Nutrition Department, he had given her extra paid hours, "passionate Iron Guard member" (Dr. Iac., Assistant at the the equivalent of a part-time job, [but] from the date of physiology department, tel. 3.27. 90 ,home, can give January 1, 1955 to September 1, 1955, he obliged her to give references about this). In the bourgeois army, he was highly him 1/2 of her part-time wage. G. Maria told me this out of regarded because of the wealth he still holds, to a great despair because (redacted by the CNSAS) his fabulous wealth extent: helped him back the interests of the Iron Guard. [And] after - Mansion in Călimanesti she gave him this money, "which he literally grabbed from - Estate and mansion in Bran her and which were part of her due", as a reward, assoc.prof. - Houses in Bucharest Gonţea gave her the sack. The reason was another - Car etc. subordinate, dr. Şuţescu Paraschiva (anonymized words by the CNSAS) who [becoming a favorite] continued to work Later on, Assoc. Prof. I.G. proved to be a hostile element, with I.G. G.Maria told me all this on the way between pleading in favor of Antonescu's criminal actions against the Ardealul Avenue and Plevnei Street, as she was going USSR. References: Dr. Eug. D. and Dr. P. towards Progresului to the Rectorate of the Institute of Thus, Assoc. Prof. Gonţea maintained ties with his former Medicine and Pharmacy. collaborators from the Legionary Nest, Assoc. Prof. Pr. Gh., 5) At the Nutrition Department, Assoc. Prof. Gonţea sells from the Physiology Department, with Tudor G., also from overpriced wool and veal meat from his estate in Bran to the the Physiology Department, with G. Maria from the same staff, whom he obliges to buy, threatening to treat them department, about whom I will tell you in detail further badly if they don't. Assist. A. C. can give references, phone down. Assoc. Prof. I.G. has remained the same reactionary 3.11.10. person, nurturing sympathy for the Iron Guard, and still indulging in hooliganism. Here are some facts: 6) (Anonymised paragraph by the CNSAS) G. Maria was a notorious Iron Guard member, the daughter of the richest 1) He encourages the personnel not to apply for higher merchant in Constanța who lived in the countryside in positions since exams are "based on the Russian model and Bulgaria until 1956, when she brought him back to Bucharest have a temporary character". References can be given by C. for good since "rich people are no longer oppressed as they Adrian, assistant at the Physics Faculty, phone 2. 68.09 used to be", according to her own words. G. Maria worked 2) Assoc .prof. I.G. sent two articles for publication to the with the Legionnaires, being... (redacted). Thus she helped Institute of Physiology of the Academy of the R.P.R. (People's them set up camps in the V. Roaită resort and her father Republic of Romania), registered with no. 36 / 6.III.1957 of helped by providing food and transportation. the Nutrition Department: 7) As far as his behavior towards students is concerned, I can - The bibliography of the first article includes 13 works, none mention that several of them have lodged complaints about of them Soviet. his demagogic manifestations with the Dean’s Office of the

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Faculty of Medicine, but to no avail. References can be given auspicious to acts of dissent, especially from those who had by student P. Aurel from the sixth year. His attitude towards had certain political views in the past, even if they had let the young employees of the Institute of Medicine and themselves be carried away; on the contrary, it meant Pharmacy has remained fierily reactionary and he is doing increased vigilance8. his best to exclude those who had worked in ministries Ellyˊs denunciations were obviously not based on representing our régime. I am attaching the original "proletarian intransigence" or "ethical" reasons, but rather statements by Prof. N., whom Assoc. Prof. Gonţea Iancu told on personal, vindictive motives, which, after so many years, that he would do his best so that Dr. Maria Mih. and her cannot be properly weighed. It is possible, however, that the husband, C. Adrian, who had worked at the MAI [Ministry of "witnesses" mentioned by the informer may have Internal Affairs ] would be sacked. C. Adrian was summoned considered themselves, for various reasons, harmed by the to the C.C. of the P.M.R. for a mission, which Gonţea branded teacher (possibly by the exigencies that he imposed) or as a dangerous element for the reactionary clique he is a "stopped" in their desire for rapid ascension in the member of. (I should mention that the summons took place professional field or on the social ladder. In that period, the a few months after the appointment of assistant C. within "weapon" at hand chosen by an informant in ensuring his the Medicine Faculty). success was invoking an alleged Iron Guard activity, or at 8) About Assoc. Prof. Gonţea Iancu's son, whose name is least sympathy, on the part of the "target". Gonţea Liviu, a fourth-year student at the Faculty of One of the graduates of the Faculty of Cluj (whose name was Medicine, I know that he was under investigation by the blacked out), was "promoted", as early as his student years, Ministry of Internal Affairs over hooliganism when he was a to a party activist, to the "Central Committee structure”! high-school student. I mention that Gonţea Iancu was Starting in 1949, he held important positions in the state connected to Lupaş Tudor, who provided him with articles hierarchy: adviser to the minister of Health, then Sanitary translated from Hungarian, which had been broadcasted on General Inspector. He became pro-rector of the Institute of the radio, which Gonţea Liviu handed to the students in his Medicine and Pharmacy in Bucharest (IMF) then, based on group. In a conversation with Tudor Geor., Lupas's uncle, this rapid ascension and, of course, "being a valuable who worked in the physiology laboratory, told me that «the person", was named associate professor. (This rapid fast- guilty people are free while his nephew is in prison.» lane promotion took barely six years).Since 1955 he engaged When I asked him if Gonţea’s son had been involved, he did in research as head of department at the Hygiene and Public not give a straight answer, but made me understand that he Health Institute in Bucharest. How could "Elly” not cite his had." name and indicate him as a credible witness in order to assess professor Gonţea's activity and behavior? (signed) Elly And what about another rival, born in 1884? The latter We find ourselves in 1957, a few months after the Hungarian hoped that, thanks to the protection of his administrative revolution (called "counter-revolution" by the Communists), superiors and by "revealing" I.G.'s alleged "Legionnary when the vigilance and coercive measures of the Securitate activity" and backing Elly's allegations, he could indefinitely got a new "boost", stimulating the activity of informants. extend his teaching term, in no matter what department, if Moreover, on October 27, 1956, in university cities, students Gonţea could be forced to give up the position he held were out in the streets demanding an improvement in living «based on merit». conditions, the removal of the Russian language from the educational curricula, and the liberalization of social life, Nevertheless, we should mention that Ellyˊs detailed demands which were followed by reprisals and arrests. statements found in this file were not backed by any "notes" Students and professors thus becoming a target of the newly or testimonies given by the witnesses she cited. established Ministry of State Security, an institution distinct After August 23, 1944, the issue of the legionnaires had from the Ministry of Internal Affairs, at the time led by become a major concern for the new power. In 1945, former Alexandru Draghici. legionnaire’s members who were deemed as dangerous A year later, in June, a plenary session of the C.C. took place, were arrested and sent to labour camps. Others were to be announcing a return to the struggle against bourgeois determined to become – and truly became – collaborators ideology, criticism of intellectuals accused of snobbery, of the Communist Party, following Ana Pauker's cosmopolitanism, apoliticism, negativity etc. Thus, the intervention. On December 10, 1945, the Ministry of Internal departure of the Soviet troops who had been stationed on Affairs issued an order "legalizing" some of the former Iron Romanian territory for 14 years, did not seem to be Guard members, who no longer posed a threat to the State

and who had offered their services to the new régime. It was Puşcariu), shared rightist, or even Iron Guard sympathies, an a bluff: the trio made up of Ana Pauker, Teohari Georgescu ideological confusion which they later regretted; among (minister of Internal Affairs) and KGB general Nicolski were them there were also many physicians who had acquired later accused of having facilitated the infiltration of former some notoriety in their profession. Iron Guard members into the Communist Party. As a ** consequence, the three former Communist dignitaries were ousted. I once asked an older friend: why is there so much hatred towards a man who, through his knowledge and hard work, At that time, however, the Legionnary Movement ghost had dedicated his life to medicine for the public welfare? reappeared and informant "Elly" seized this opportunity to accuse Iancu Gonţea. It is true that many intellectuals, – "The he lazy man will throw stones only at the tree full of particularly younger ones, had sympathized with the fruit, so that he can collect the fallen fruit effortlessly", my Legionnary Movement in the 1930s, even though they later friend replied. "And then, we know from the Gospel that 'no disavowed this affinity (see the notorious cases of Mircea good tree will bear bad fruit, nor will a bad tree bear good Eliade, Eugen Ionesco, Emil Cioran.) Many intellectuals from fruit.'" the area of Braşov – Bran (eg, the great philologist Sextil

References:

1. Stoian, Emil, „Portrete din Bran”, Dealul Medicilor Publishing 6. Ib. id. Reper 2 House, Braşov, 2002 7. National Council for the Study of Security Structure Archives 2. Mihailide, Mihail, „Insolitul ospăț al unui devorator de arhive”, (CNSAS), Central Archives Department, Operative file Gonţea Ion- Viaţa Medicală Românească Publishing House, 2017 Iancu, cote 498910, vol.I and vol.II * The files were studied by 10 3. Ibidem other people between April 5, 1969 and March 3, 1976). 4. Medicine History Documentary Library, National Institute for 8. Collective, coordinator Valentina Bilcea, „Istoria românilor. Public Health, Bucharest, Iancu Gonţea File. Date Fapte. Oarneni”; Foreword: Professor Adrian Cioroianu Ph.D., Meronia Publishing House, Bucharest, 2018 5. Ibidem

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

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Romanian Journal of Military Medicine

New Series, Vol. CXXII, No 2/2019, August ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126