Doctoral Thesis Summary

MODERN MANAGEMENT IN THE

SURGICAL TREATMENT OF THE

MALIGNANT GLIOMAS

Scientific Coordinator:

PhD MD Ion POEATĂ PhD student:

Maria-Raluca Bolotă

(Munteanu)

IAȘI

CONTENT

CONTENTS i

List of abbreviations iv

THE GENERAL PART

CHAPTER I

INTRODUCTION 1

I.1 Cerebral tumors 1

I.2 Cerebral gliomas 1

I.2.1 Anaplastic astrocytoma 3

I.2.2 Glioblastoma 5

I.2.3 Gliosarcoma 5

I.3 Glioblastoma 6

I.3.1 General data about glioblastomas 6

I.3.2 The epidemiology of glioblastomas 6

I.3.3 The etiology of glioblastomas 7

I.3.4 The genetics of glioblastomas 8

I.3.5 Biological and morphogical characteristics 9

I.3.5.1 The Proliferation 9

I.3.5.2 The Invasion 10

I.3.5.3 The Angiogenesis 11

I.3.6 Molecular subtypes of glioblastomas 12

CHAPTER II

THE DIAGNOSIS OF GLIOBLASTOMAS 14

II.1 Clinical diagnosis 14

II.2 Imagistic diagnosis 15

II.2.1 Computed Tomography (CT) 15

II.2.2 Magnetic Resonance Imaging (IRM) 16

II.2.3 Positron emission tomography (PET) 19

II.3 Anatomopathological diagnosis and histological subtypes 20

II.4 Differential diagnosis 23

CHAPTER III

MULTIMODAL TREATMENT OF GLIOBLASTOMAS 24

III.1 Surgical resection 24

III.1.1. Preoperative evaluation 24

III.1.2 Surgical techniques 24

III.1.3 Surgical adjuvant systems 25

III.1.3.1 Intraoperative monitoring 25

III.1.3.2 Intraoperative ultrasound 27

III.1.3.3 Neuronavigation 28

III.1.3.4 5- ALA Applications in brain malignant tumors 32

III.2 Radiotherapy 34

III.3 Chemotherapy 35

III.3.1 Temozolomide 35

III.3.2 Carmustine 35

III.4 Prognosis in glioblastomas 36

CHAPTER IV

NEW THERAPEUTHICAL TREATMENTS IN MALIGNANT GLIOMAS 38

IV.1 Immunotherapy 38

IV.2 Anti-angiogenesis strategies 39

IV.3 Apoptosis induction of malignant glioma 39

THE PERSONAL PART

CHAPTER V

MOTIVATION AND AIMS OF THE DOCTORAL STUDY 41

V.1 The motivation of the doctoral study 41

V.2 The aims of the doctoral study 42

CHAPTER VI

MATERIAL AND METHOD 43

VI.1 Inclusion Criteria 43

VI.2 Exclusion Criteria 43

VI.3 Studied lots 43

VI.4 Side effects 44

VI.5 Planning preoperative – The Neurosurgical equipment modified in the

Operating Room 45

VI.6 The principles of the intraoperative neuronavigation 48

VI.7 The intraoperative ultrasound 53

VI.8 Microsurgical technique approach (particularities, general management and

complications) 56

CHAPTER VII

RESULTS 57

VII.1 General characteristics of the studied lots 57

VII.2 Statistical results 58

VII.3 Particularities of the studied lot 99

VII.4 Presentations of particular and enlightening cases 101

CHAPTER VIII

DISCUSSIONS 115

CHAPTER IX

CONCLUSIONS 128

CHAPTER X

THE IMPORTANCE AND ORIGINALITY OF THE THESIS 129

BIBLIOGRAFY 131

The doctoral thesis is illustrated through 36 tables, 143 figures and 142 pages. The

summary reproduces selectively the iconography and bibliography of the text respecting the

numbering and the contents of the thesis in extenso. The bibliographical references present are

identical with the existent ones in the doctoral thesis.

Key-words: Glioblastoma, Acid 5- aminolevulinic (5-ALA), Gliolan, Neurosurgery,

Neuronavigation

INTRODUCTION

Malignant brain gliomas

Malignant brain gliomas are tumors with invasive character, which lead inevitably to

death in 1-2 years after diagnosis (Kleihues P., 1999). These tumors are associated with a weak

prognostic, despite the maximal, surgical treatment completed with radiotherapy and

chemotherapy. The resection grade of the tumor is accepted as essential for the optimal surgical

treatment, and recent studies offers level II evidence in favor of a cytological maximal

reduction in the management of the new diagnosed malign glioma. (Mc Girt et al., 2009;

Stummer at al., 2008; Stummer at al., 2009). The first case of cerebral glioma in which surgical

resection was performed belongs to Rickman Godlee in 1884. (Godlee at al., 1884).

The malign glioma treatment is not representing just from the surgical resection, but

nowadays it`s existing like gold standard the multimodal treatment (radiotherapy,

chemotherapy), taking into consideration the fact that the best treatment option is the resection

as extent as possible of tumor volume, keeping in this way the morbidity minimum level. In

the literature existing a lot of evidences which lead to the fact that a maximal surgical

cytoreductive technique (over 98% of the initial mass of the tumor) is an important prognostic

factor for the patient’s survival (Kleihues P., 1999). Due to the infiltrative character of these

tumors this thing is not easy to count and to accomplish.

The target of this chosen theme for study in this doctoral preparation it is a pathological

surgical issue frequently met in the medical practice, represented by the modern management

neurosurgical techniques of the malignant glioblastomas.

In Stummers’s et al. in the paper “Counterbalancing risks and gains from extended

resections in malignant glioma surgery: a supplemental analysis from the randomized 5-

aminolevulinic acid glioma resection study”, published in 2011 (Stummer W T. J., 2011)

realized a prospective randomised phase III trial where he found out the same results which are

trying to follow in this doctoral thesis. In this way, he showed that the surgical treatment guided

by fluorescence induced by 5-aminolevulinic acid (5-ALA) reach achieve easier a maximal

resection, than using the conventional microsurgical treatment with the white light. In the same

time, the studies published by the international literature obtain the same results (Stummer et

al., 2006; Díez Valle et al., 2013; Hefti et al., 2008; Wen et al., 2008;). Maximal resection of

malignant glioma using 5-ALA was proved to be the best technique in nowadays, which has a

longer free time without relapse and a longer survival rate.

The targets of this doctoral study

The investigations followed in the surgical treatment will be structured in the next

directions of researching:

The principal targets:

The principal targets of this doctoral study were linked to the effectiveness of

applicability of interventional methods at Clinical Emergency Hospital „Prof. Dr. N. Oblu” Iasi

at the Neurosurgery Department in the brain malign gliomas area, for evaluate the

improvements in the survival rate through a maximal resection.

Another main objective is that one who is linked by effectiveness study of the

administration multimodal treatment at the patients who were undergone the resection with

conventional method versus those one who had undergone resection guided by fluorescence

induced by 5-aminolevulinic acid (5-ALA). One the other hand, here were highlighted the

specificity and the sensitivity the variety of guided methods. All of these providing supports to

the feasibility of the proposed study.

Another principal target is represented by statistical analyzed of the results, for clinical-

imagistic correlations with a high accuracy. After all, we will adapt in this way the surgical

protocols through obtaining positive results for the patients.

The secondary targets:

Improvement of the patients’ tracking protocol from an imagistic point of view

(imagistic controls performed according to an established schedule), who are imagistic

diagnosed with cerebral malignant gliomas, operated in the hospital and its implementation in

the neurosurgery department. The clinical investigations of the efficiency of this protocol was

performed on short time (3 days) and long time (1 year) and included applied interventional

methods (the neurological, imagistic and functional evaluation of the patients).

It will be study the following:

The protocols and therapeutic algorithms used till in this moment in the resection

of malignant gliomas, and the obtained data will be compared with those which are

published in the literature;

The asymptomatic arterial cerebrovascular complications and the symptomatic ones

which are associated with the tumor pathology in preoperative and postoperative

time;

The role of the prevention of the postoperative cerebral edema and the pulmonary

embolism, like a possible complication which can be associated with the surgical

intervention or the anesthesia;

The secondary side-effects on short term and long term of the 5-ALA administration

and its influence on the patient’s neurological status;

The association between the postinterventional neurological deficit and the patient’s

quality life;

The neuromotor recovery to those patients who were undergone microsurgical

resection, showed through by international Karnofsky Score;

The establishing of correlations between the early imagistic diagnostic and on the

long term of the patients and their survival rate. One the other hand, we can adding

to follow the post operator complications (local and distance).

Material and method

1. Inclusion Criteria

At the Neurosurgery Hospital “Prof. Dr. N. Oblu” Iasi, based-image malign glioma

diagnosed patients were included in study and explored both in the neuroimaging department

of the hospital and externally.

We mention some of the inclusion criteria:

Patients to whom the image-based malign glioma suspicion was raised, who

also have surgical indication, lending to 5- ALA resection

Young patients with a history of recurrent malignant glioma, with a favorable

neurological status;

Based-image diagnosed malign glioma patients, which lies in the functional area

with surgical indication and with the use of 5- ALA, associated with modern

intraoperator techniques (neuronavigation, intraoperative ultrasound,

intraoperative monitorization);

The conditions under which the present subjects fit in the selection criteria and agree to

take part at the clinical trial, they sign their consent regarding both the surgical intervention

and the 5- ALA administration and their logging will be done in the database.

2. Exclusion criteria

Out of the exclusion criteria we mention:

• the refusal of subjects with malignant glioma or their families to be included in the clinical

trial after having been informed of the procedure and the risks involved;

• patients with a history of allergy to any of the 5-ALA compounds, after detailed

anamnesis;

• patients with porphyria or history of porphyria in the family;

• patients with acute or chronic hepatopathy, after studying the biological profile;

• patients who have been diagnosed with psychological illness or psychiatric illness as a

result of the psychological examination at the clinic;

• non-cooperative patients who have cerebral functional areas affected by tumors and have

not been accompanied by compliant families able to understand and assume the exposed

technique;

• people without stable residence;

Although there are patients who meet all the requirements of the inclusion criteria, the

presence of a single exclusion criterion determines the impossibility of belonging to the

presented study.

3. Studied lots

The present thesis study was based in the Clinical Emergency Hospital ,,Prof. Dr. N.

Oblu’’ in Iași, in the I, II and III neurosurgical clinics, in the period 1 January 2013 to 1 May

2015.

The first study of the thesis was retrospective and was performed on a total of 110

selected patients from the hospital archive, diagnosed with high-grade glioma that were

operated by the classical interventional method during January 2009 - December 2011. The

second study is one prospectively conducted on a lower batch of 17 patients from the clinics

mentioned above between 2013 and 2015, in which imaging of glioblastoma suspected and

surgical maximum resection was performed following administration of 5 -aminolevulinic

(Gliolan®). The 17 surgical interventions used modern hospital equipment and advanced

neurosurgical techniques (intraoperative ultrasound, neuronavigation and intraoperative

monitoring).

Fig. 6.1. Intraoperative microscope integrated into the complex neuronavigation system (hospital

equipment)

Fig.6.2, 6.3 Intraoperative images of resection in blue light.

Fluorescence of tumor infiltrated brain tissue is observed

Results and discussions

In the database created for this study, data were entered about patients such as: name,

sex, age distribution (20-30 years, 31-40 years, 41-50 years, 51-60 years old, 61 -70 years, 71-

80 years), tumor localization by dominant hemisphere, onset symptom, interval from first

symptom to doctor presentation, anatomical location of the tumor (frontal, parietal, temporal,

insular, occipital), structure (Biopsy, subtotal resection, total resection), use of ultrasound for

total resection - echocardiography, macroscopic aspect of tissues, the number of lobes affected,

localization in functional areas, invasion of basal nuclei, invasion of vascular structures,

Microscopic tissue appearance, histopathological diagnosis, postoperative complications,

postoperative status, control data, radiotherapy, radio and chemotherapy treatment,

chemotherapy treatment C, reintervention data, recidivism data (no. Months), imaging aspect

- tumor aggression (correlation), free time of symptoms, survival rate. All of these data and not

only were taken into consideration to analyze the 5-ALA effects on the health of the patients

who were treated in our surgical center.

The statistical study was performed on a retrospective group of 110 patients diagnosed

with glioblastoma and operated, respectively on a prospective group of 17 patients with the

same diagnosis of resection and administration of Gliolan®. Statistical analysis was performed

in SPSS 20.0.

For the statistical analysis of the relevant data on the treatment of the patients included

in the study, classical and new data processing and statistical analysis methods were used to

obtain relevant results on the achieved objectives.

The study confirms the data from the literature on the age distribution of malignant

gliomas, a peak between 51-60 years, and only 4.5% at the young ages of 20-30 years.

Malignant gliomas have been found to be most commonly located in the frontal and temporal-

frontal region of 46.4%. All patients were subjected to surgical treatment and maximum

microscopic resection was performed in the 17 patients receiving Gliolan®. The study found a

good quality of life, prolonging the non-relapse survival rate to 1.7 years. The survival rate at

12 months was 100%, at 16 months 2 patients were lost, the study continues.

The first group, consisting of 110 patients, consisted of 61 men (55.5%) and 49 women

(44.5%) - Fig. 7.1, aged between 20 and 80 years - Fig. 7.2. The largest proportion of patients

with glioblastoma was enrolled in the age range of 51-60 years, the lowest (5 patients and 4.5%)

aged between 20 and 30 years.

Fig. 7.1. Batch structure by gender

Fig. 7.2. Batch structure by age range

men55,5%

women44,5%

20-30 years4,5%

31-40 years15,5%

41-50 years10,9%51-60

years34,5%

61-70 years19,1%

71-80 years15,5%

Regarding the comparative distribution of patients by age and gender (Figure 7.3), it

can be seen that in men the most cases were also recorded in the age range of 51-60 years,

while in women, in addition to this age range, an equal percentage of patients aged 61-70 years

is added. It can also be noted the high percentage (19.7%) of older men (between 71-80 years),

a phenomenon whose presence has not been identified in women as well.

We also studied the nature and severity of onset symptoms (Figure 7.70). The most

common onset symptoms were paresis and motor deficit, identified in 40 patients (36.4%),

followed by various types of seizures, identified in 38 patients (34.5%), HIC or headache (30

patients, 27.3%). Confusional syndrome was identified in 21 patients (19.1%), anamnestic

disorders in 14 patients (12.7%), and dysphasia or aphasia in 13 patients (11.8%).

Fig. 7.70. Batch structure based on onset symptoms

Patients were subjected to more detailed monitoring by periodic MRI examinations

(Figure 7.71) - 3 weeks (1 case), 3 months (6 cases), 6 months (3 cases) and 9 months (2 cases).

Fig. 7.71. Structure of the batch according to the time of MRI examination

12,7%

27,3%

11,8%

34,5%36,4%

19,1%

0,0%

5,0%

10,0%

15,0%

20,0%

25,0%

30,0%

35,0%

40,0%

0

1

2

3

4

5

6

7

RMN la 3 sapt RMN la 3 luni RMN la 6 luni RMN la 9 luni

In 4 patients (22.2%) the tumor was located frontally and temporally; The most frequent

localization was parietal, present in 5 patients (27.8%), there was also a patient with localized

and occipital localization (Figure 7.74). Two patients (11.1%) were diagnosed with location on

the median line (CC), and also 2 patients had 2 affected lobes, and 2 were affected by one

single lobe.

Fig. 7.74. Batch structure based on tumor location

All patients were operated between 2013 and 2015, with most (66.7%) operating in

2014; In 2013, 22.2% of the patients were operated and 11.2% in 2015.

After surgery, biopsy of extirpated specimens was performed. In 8 cases (44.4%) of the 17

resection was performed (Figure 7.79).

Fig. 7.79. Batch structure based on the use of the maximum resection procedure

22,2%

27,8%

22,2%

5,6% 5,6%

0,0%

5,0%

10,0%

15,0%

20,0%

25,0%

30,0%

frontal parietal temporal insular occipital

no55,6%

yes44,4%

Conclusions

1. A challenge in today's modern neurosurgery is to establish protocols for the management

of patients diagnosed with cerebral malignant glioma and their correct implementation at

hospital level. The surgical resection of malignant gliomas using 5-ALA (Gliolan®) is a

new, successful technique introduced for the first time in Romania at the Emergency

Clinical Hospital “Prof. Dr. N. Oblu " Iasi.

2. From our experience, 5-ALA is a well-tolerated substance by patients, and fluorescence-

guided tumor resection procedures if well implemented will in the future provide a current

glioblastoma operative technique and inclusion in the binding protocol of the hospital.

3. According to our findings, 5-ALA is an intraoperative tumor marker that reliably guides us

towards an effective cost-benefit innovation, being well above classical resection.

4. Neuronavigation was used in over two thirds of patients, being useful for the minimal

invasive surgery and the choice of the pathway.

5. In the researched cases it was found that the resection of malignant gliomas with

localization near the cerebral functional areas, when accompanied by intraoperative

imaging (ultrasound, neuronavigation), we obtained better neuro functional results.

6. Intraoperative neurophysiological monitoring was used on a case-by-case basis,

postoperative patients did not show worsening of neurological deficit or Karnofsky score

decrease.

7. These techniques, combined, constitute a new therapeutic strategy to achieve positive

outcomes in the diagnosis and survival rate of patients with malignant brain tumors.

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ANNEX. LIST OF PUBLISHED WORKS

Raluca Maria Munteanu, Lucian Eva, Bogdan Dobrovat, Alin Iordache, Liviu Pendefunda,

Nicoleta Dumitrescu, Doina Mihaila, Cristina Maria Gavrilescu, Ion Poeata. (2017). Longer

survival of a patient with glioblastoma resected with 5-aminolevulinic acid (5-ALA)-guided

surgery and foreign body reaction to polyglycolic acid (PGA) suture. Rom J Morphol Embryol,

58(X):Y–Z , accepted for publication, ISI factor 0.811

M. Dabija, L. Eva, I. Poeata, Alina Paiu, V. Dorobat, Raluca Munteanu. (2017). Unusual

aggressive and rapidly growing glioblastoma multiforme-case presentation. Romanian

Neurosurgery, Vol. XXXI, Nr. 1, 2017.

Munteanu Maria-Raluca, Poeata Ion, Pendefunda L., Eva Lucian, Iordache Alin-Constantin,

Turliuc Dana-Mihaela. (2015 November 19-21). Neurosurgical Treatment of Glioblastomas

Using Neurophysiological Monitoring, Neuronavigation, Radiosurgery and Fluorescence-

Guided Surgery with 5-Aminolevulinic Acid. The 5th IEEE International Conference on E-

Health and Bioengineering - EHB 2015, 978-1-4673-7545-0/15, Indexed in IEEE, ISI

Proceedings.

SCIENTIFIC PAPERS PRESENTED

Munteanu R., Eva L, Utilizarea Giolanului în tratamentul tumorilor cerebrale. Simpozion de

Neuroștiințe , Iași 29-31 Octombrie, 2015

Munteanu R., Eva L., Turliuc D., Iordache A., Dumitrescu G., Poeată I. The resection of

Malignant Gliomas Using 5-Aminolevulinic Acid (5-ala, Gliolan). 41 st Congress of the

Romanian Society of Neurosurgery, June 3rd-6 th 2015, Iași

Munteanu R., Eva L., Dobrin N., Chiriac A., Managementul modern al stroke-ul ischemic.

Zilele Spitalului Clinic de Urgență ,, Prof.Dr. N.Oblu “ ,Iași ,24-26 Octombrie 2013

Eva L, Munteanu R ,Poeată I., The resection of malignant gliomas using 5-Aminolevulinic

Acid( 5-ALA, Gliolan), Conferința de neuroștiințe cu participare internațională, 20-22

Octombrie 2016

Sorete R.,Dobrin N., Cucu A., Munteanu R., Turliuc D., Right Hemisferic Glioblastoma As

Intracerebral Hemorrage: Case Report. 41 st Congress of the Romanian Society of

Neurosurgery, June 3rd-6 th 2015, Iași

Eva L.,Turliuc D.,Lungu R., Munteanu R., Dumitrescu G., Cucu A., Meningiom frontal gigant

stâng cu rezecție totală Simpson I și duroplastie prin utilizarea de agent de etanșare Vivostat,

Conferința de neuroștiințe cu participare internațională, 20-22 Octombrie 2016

Cucu A., Munteanu R., Eva L.,Turliuc D., Anatomia chirurgicală a zonelor sigure de acces

către trunchiul cerebral. Conferința de neuroștiințe cu participare internațională, 20-22

Octombrie 2016

Eva L,Bișoc O.,Turiuc D., Munteanu R. Tratamentul neurochirurgical al Bolii Parkinson,

Simpozion de Neuroștiințe , Iași 29-31 Octombrie, 2015

Iordache A., Munteanu R., Dobrin N., Ultrasonografia în neurochirurgie. Simpozion de

Neuroștiințe , Iași 29-31 Octombrie, 2015

Eva L,Bișoc O.,Turiuc D., Munteanu R. Stimularea cerebrală profundă-rol în tratamentul

Bolii Parkinson Simpozion de Neuroștiințe , Iași 29-31 Octombrie, 2015