High grade glioma (HGG) still represent a challenge for the medical community worldwide.1, 2, 3, 4 Currently, average survival rates reported for anaplastic astrocytoma (AA) and glioblastoma (GBM) are 3–4 years and 10–16 months, respectively.5 One of the greatest concerns remains the lack of knowledge about the etiopathogenesis and pathophysiology of gliomas. The new WHO classification tried to explain the biological behavior of these tumors, analyzing their metabolic and genetic pathways.5 However, such classification has determined further fragmentation of our knowledge, in a time when we need a minimum common denominator to solve this terrible puzzle.6,7 In recent years, research focused on glioma neuroradiological features trying to relate these with their biological behavior.8, 9, 10, 11, 12, 13, 14, 15 As a consequence, many preoperative information about low grade gliomas (LGG) came from analysis of velocity of diametric expansion (VDE). Pallud and Mandonnet16, 17, 18, 19 reported a strict correlation between VDE and glioma aggressiveness: growth values under 4 mm between two consecutive MRI studies suggest a low invasiveness rate and thus lower malignancy.20,21 However, the same evidences are not available for HGG because of the lack of several preoperative MRI and no growth patterns have been standardized for HGG. We report a series of four patients in whom HGG growth and evolution were radiologically analyzed thanks to a long preoperative follow-up since tumor diagnosis until treatment.
We describe a series of 4 patients followed by the first author from 2014 to January 2019. Two patients are male, two are female, two had a pathological diagnosis of GBM, one of AA and one received a neuroradiological diagnosis of GBM. Every patient was radiologically followed through almost three pre-operative MRI scans, focusing on T1 with gadolinium and T2/
It represents the reverse formula of ellipsoid volume formula calculation:
Variation of MTD
Where n is the ordinal number of MRI scan for each patient.
Velocity of diametric expansion (VDE)18,20, or MTD difference over time (days) between two consecutive MRI scans, was calculated as:
where ΔT is the number of days between two consecutive MRI scans. VDE is reported as millimeters on days (mm/dd). Assuming a linear VDE growth, VDE for each interval of time was then calculated respect to 1-solar-year, as follow:
For each patient, mean acceleration (Acc) or VDE variation over time, was calculated as follows:
Where
In order to evaluate variation of VDE and Acc along observation time, further analysis were conducted for any patient. In particular, we observed peak of VDE and Acc values in all patients.
About VDE, we quantified these peaks highest value of VDE /mean VDE value ratio (listed in Table 3) in every patient along observation period, expressed as percentage [eq. 6]:
Where
In Acc peak analysis, we evaluated ratio between highest Acc value and mean Acc value for any patient (listed in table 4), expressed as percentage, as follows:
Where α is the Acc value; αmax is the highest value of Acc recorded for any patient along all observation period;
Further analysis evaluated EN/FLAIR volumes ratio (EFVR) (eq. 8), EN/FLAIR MTD ratio (EFMR) and their evolution over observation time (eq. 10 and 11), as follows:
Where n is the ordinal number of MRI scan for each patient; n0 and nf are the first and last MRI scan for each patient, respectively.
Every analysis was conducted for whole-tumor FLAIR volume and for single EN. The analysis and graphic representation were carried out with Microsoft Office Excel® software.
In addition, a literature review was performed using PubMed MEDLINE database and searching for “radiological glioma growth”, “glioma radiologic follow-up”, “glioma volume growth”.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
A 39 y.o. male patient was under radiological follow-up since 5 years after meningioma resection. MRI scan was obtained once a year. After 5 years of negative post-operative MRI, the exam showed hyperintensity in the right hippocampal and para-hippocampal areas on T2/FLAIR sequences, without enhancement after gadolinium infusion. MTD was 35.5 mm. For the sake of a closer follow-up, a new MRI scan with spectroscopy was scheduled 3 months later. In this second MRI scan, the FLAIR hyperintense lesion MTD was 39.7 mm, with no enhancement after gadolinium injection. Spectroscopy showed a peak in N-acetyl-aspartate (NAA), choline (Cho) and Creatinine (Cr) values. Both data suggested a likely diagnosis of ex novo HGG. Despite strong recommendation to undergo surgery, the patient delayed surgical treatment by 3 months. The new MRI scan, obtained the day before surgery for surgical planning, showed a MTD of 45 mm and contrast enhancement on T1-weighted sequences. The post-operative MRI showed a complete resection of the enhancing tumor. After resection, histopathologic diagnosis revealed AA, wild-type (WT) for IDH1. All values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] are listed in Table 1. After tumor gross total resection, the patient underwent the Stupp regimen for adjuvant treatment and died 16 months later.
A 37 y.o. male patient, after an episode of dysarthria, underwent a neuroradiological workout. MRI images showed a left fronto-parieto-insular enhancing lesion suspicious for ex novo GBM. FLAIR and EN MTD were respectively 56.59 mm and 42.02 mm. After a week, he repeated the MRI with spectroscopy showing elevation of Cho and reduction of NAA values, elevation of Cho/NAA ratio, mild elevation of lactate signal. At the same time, central necrosis was visible. A diagnosis of GBM was made. FLAIR and EN MTD were 59.83 cc and 48 cc respectively. VDE was 169.23 mm/year for FLAIR tumor volume, whilst for EN was 311.81 mm/year. Due to poor neurological condition and tumor location, surgery was avoided. Following further neurological deterioration, he underwent a new MRI scan 2 weeks later. FLAIR tumor MTD was 72.60 mm, EN MTD was 52.16 mm. At this point, chemotherapy with temozolmide (TMZ) started. About two months later, a repeat MRI study showed good response. MTD was 67.37 mm for FLAIR tumor volume and 43.80 mm for EN, in which TMZ effect was higher (Figure 1). In fact, ΔMTD was - 5.22 mm and - 9.36 on FLAIR and EN nodule volume, respectively. Values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] for every MRI scan are listed in Table 1, divided for FLAIR and EN volumes. 6 months after initial diagnosis the patient remains alive.
Figure 1
MRI scans in Patient 2 at 0

Data about patient #1, #2, #3, #4
Acc = acceleration; MRI = magnetic resonance imaging; MTD = mean tumor diameter; ΔMTD = variation of MTD respect to previous value; VDE = velocity of diameter expansion; V EN = volume of enhancing nodule post gadolinium; V FLAIR = volume of fluid attenuated inversion recovery altered regions
A 72 y.o. female patient, after a seizure, underwent MRI workout without pathological findings. She repeated a MRI scan after 15 months and a FLAIR alteration in the left motor areas was seen. MTD was 21.25 mm. She refused any treatment. MRI scan was repeated further 9 months later showing a bilateral alteration of FLAIR signal in the frontal lobes. MTD was 26.30 mm. However, the patient chose to undergo neuroradiological follow-up rather than surgery. After two months, a new MRI scan showed an EN in the right frontal lobe. MTD of EN was 8.43 mm, MTD of FLAIR altered regions was 32.01 mm. Neurosurgeons suggested excision of the EN, but the patient refused again. Further MRI scans at 2, 6 and 10 weeks were obtained. MTD of EN were 11.19, 17.54 and 21.40 mm, respectively. MTD of FLAIR-altered regions were 35.73, 41.68 and 41.68 mm, respectively (Figure 2). At the end complete resection of EN was obtained; histopathological diagnosis was compatible with GBM, IDH1 WT. She underwent adjuvant therapy according to the Stupp regimen and remains alive 31 months after the index surgery. All values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] for every MRI scan are listed in Table 1, divided for FLAIR and EN volumes.
Data on fluid attenuated inversion recovery (FLAIR) tumor and enhancing nodule (EN) volume velocity of diameter expansion (VDE). Reported as mm/year
Figure 2
MRI scans in Patient 3 at 0

A 56 y.o. female patient underwent MRI for persisting headache. An incidental slight alteration of FLAIR signal in the left gyrus rectus was discovered. MTD was 7.37 mm. She repeated an MRI 5 months later to evaluate tumor evolution and an EN appeared in the previously FLAIR-altered area. MTD of the EN was 7.37 mm, whereas MTD of FLAIR-altered area was 12.6 mm and there were no further changes in the next MRIs. An MRI with spectroscopy was obtained one month later and this suggested a GBM. The new MTD of the EN was 8.43 mm. Surgical treatment was then proposed. She underwent preoperative MRI for neuronavigation one month later. MTD of the EN was 8.43 mm (Figure 3). Complete resection of EN was carried out and histopathological diagnosis revealed GBM IDH1 WT. She underwent adjuvant therapy with Stupp regimen and is still alive 12 months after surgery. All values of ΔMTD, VDE and Acc calculated according to equations [2], [4,] [5], [6], [7] for every MRI scan are listed in Table 1, divided for FLAIR and EN volumes.
Figure 3
MRI scans in Patient 4 at 0

Each patient underwent sequential MRI studies, with an average number of 4 scans along a mean period of 413 days. ENs were evident only in patient 2 on the first MRI study, whereas appeared at fourth, fourth and second MRI scan in patients n. 1, 3 and 4, respectively. No common time correlation between evidence of first FLAIR alteration and EN appearance was found. Median appearance time after first MRI scan was 432 days.
Final mean tumor volume, evaluated on each patient’s last T2/FLAIR MRI sequences, was 59 cc, with a median volume variation along sequential MRIs of 6.4 cc.
Mean MTD at last MRI was 41,66 mm and 24.54 mm for FLAIR and EN volume, respectively, whilst median ΔMTD along the observation period was 5.4 mm and 2.11 mm, for FLAIR and EN volume, respectively (Table 1).
Mean VDE was 39.9 mm/year and 45.2 mm/year for FLAIR volume and EN, respectively (Table 1, 2).
VDE analysis revealed peak in variation along time. Mean percentage maximal VDE/mean VDE ratio, calculated according to eq. 6, was 221.49% and 259.47% for FLAIR and EN volumes, respectively (Table 3).
Raw data about velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal VDE/mean VDE ratio could help in early high grade gliomas (HGG) diagnosis
Interval of consecutive MRI | VDE Pt #1 FLAIR | VDE Pt #2 FLAIR | VDE Pt #2 EN | VDE Pt #3 FLAIR | VDE Pt #3 EN | VDE Pt #4 FLAIR | VDE Pt #4 EN | Mean Values |
---|---|---|---|---|---|---|---|---|
35.50 | 169.23 | 311.81 | 16.68 | 0.00 | 11.93 | 16.81 | ||
17.03 | 258.82 | 104.54 | 6.66 | 0.00 | 0.00 | 10.81 | ||
32.24 | -52.97 | -94.91 | 43.39 | 64.14 | 0.00 | 0.00 | ||
64.59 | 47.84 | |||||||
155.18 | 165.74 | |||||||
0.00 | 48.53 | |||||||
28.26 | 125.03 | 107.15 | 47.75 | 54.37 | 3.98 | 9.21 | ||
125.63 | 135.36 | 324.99 | 300.00 | 221.49 | ||||
291.02 | 304.81 | 182.57 | 259.47 | |||||
240.48 |
Acceleration analysis according to [eq. 5] revealed a mean value of 0.0077 mm/dd2 and 0.0119 mm/days2 for FLAIR and EN volume, respectively. Mean percentage ratio between peak values and mean value of acceleration was 282.7% for FLAIR volume and 257.52% for EN, respectively (table 4). In patient n. 1 late occurrence of the EN didn’t allow complete evaluation of MTD variation, VDE and Acc (Figure 4).
Figure 4
Velocity of diameter expansion (VDE) variation of mean tumor diameter (MTD) for fluid attenuated inversion recovery [FLAIR] and enhancing nodule (EN) volumes for each patient. Plus the case reported by Mandonnet

Raw data of mean acceleration (Acc) based on velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal Acc/mean Acc ratio of each patient could help in early high grade gliomas (HGG) diagnosis
Interval of consecutive MRI | Acc Pt #1 FLAIR | Acc Pt #2 FLAIR | Acc Pt #2 EN | Acc Pt #3 FLAIR | Acc Pt #3 EN | Acc Pt #4 FLAIR | Acc Pt #4 EN | Mean Values |
---|---|---|---|---|---|---|---|---|
0.0003 | 0.0662 | 0.1220 | 0.00010 | 0 | 0.0002 | 0.0003 | ||
0.0005 | 0.0394 | 0.0159 | 0.00007 | 0 | 0.0000 | 0.0008 | ||
0.0015 | -0.0040 | -0.0072 | 0.00248 | 0.0037 | 0.0000 | 0.0000 | ||
0.00843 | 0.0062 | |||||||
0.03037 | 0.0324 | |||||||
0.00000 | 0.0046 | |||||||
0.0008 | 0.0339 | 0.0436 | 0.0069 | 0.0078 | 0.0001 | 0.0004 | ||
195.6695 | 195.5808 | 439.7477 | 300 | 282.7495 | ||||
280.0617 | 414.7516 | 77.74935 | 257.5209 | |||||
270.1352 |
Analysis of EFVR and EFMR, according to eq. 8–13 did not show significant results.
Ex novo HGG diagnosis usually becomes evident when the tumor mass is wide and resection must be carried out as soon as possible. Thus, for each patient no many preoperative MRI scans are available for mathematical analysis of tumor growth. In the past decades, imaging studies on LGG evolution23,24 let neurosurgeons to change their mind on treatment: from a “wait-and-see” approach to an early resection one, due to the understanding of malignant transformation risk.17,18 Indeed, Mandonnet
To our knowledge, this is the first study describing parameters of acceleration and VDE peak in a retrospective series of ex novo HGG. Through sequential MRIs and evaluation of these parameters, an early diagnosis of HGG could be done. In addition, time between consecutive MRI scans could be reduced to 15–20 days. This work represent a pilot study on new findings of HGG growth curve, never investigated, due to short observation time in case of HGG suspect. Despite limitations in number of patients and observation time, if our data are confirmed in larger series, such values could be helpful as prognostic factors in non-surgical patient. In an attempt to obtain further confirmations, a multicenter register could be create, where all data about long-preoperative-follow-up of HGG could be reported. Moreover, studies on in-vivo and invitro models could associate genome mutations with such phenotypical variation, looking for new biological tumor pathways of interest.
Figure 1

Figure 2
![MRI scans in Patient 3 at 0 (A), 465 (B), 742 (C), 790 (D), 811 (E), 825 (F) and 854 (G) days (fluid attenuated inversion recovery [FLAIR] and T1 with gadolinium sequences).](https://sciendo-parsed-data-feed.s3.eu-central-1.amazonaws.com/6062cc35282c524fbc6e2e22/j_raon-2020-0071_fig_002.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20230602T101348Z&X-Amz-SignedHeaders=host&X-Amz-Expires=18000&X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20230602%2Feu-central-1%2Fs3%2Faws4_request&X-Amz-Signature=87898036254937ba9785e14b742619dd56bccc8dba044e5c1dd6ff63e546b6ec)
Figure 3
![MRI scans in Patient 4 at 0 (A), 160 (B), 196 (C) and 223 (D) days (fluid attenuated inversion recovery [FLAIR] and T1 with gadolinium sequences).](https://sciendo-parsed-data-feed.s3.eu-central-1.amazonaws.com/6062cc35282c524fbc6e2e22/j_raon-2020-0071_fig_003.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20230602T101348Z&X-Amz-SignedHeaders=host&X-Amz-Expires=18000&X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20230602%2Feu-central-1%2Fs3%2Faws4_request&X-Amz-Signature=ed6759c9c097089018cc70e4e3fc6e7d5421ea5e0eaa0010f89e01c21d85be1c)
Figure 4
![Velocity of diameter expansion (VDE) variation of mean tumor diameter (MTD) for fluid attenuated inversion recovery [FLAIR] and enhancing nodule (EN) volumes for each patient. Plus the case reported by Mandonnet et al. as specified in Discussion paragraph. Graphic shows variation of acceleration (Acc) based on VDE (mm/days2) for FLAIR tumor volume and EN volume along time. Except obvious similar variation for two types of volume considered, peaks are easily notable. VDE of patient #1 is covered by patient #4.](https://sciendo-parsed-data-feed.s3.eu-central-1.amazonaws.com/6062cc35282c524fbc6e2e22/j_raon-2020-0071_fig_004.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Date=20230602T101348Z&X-Amz-SignedHeaders=host&X-Amz-Expires=18000&X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20230602%2Feu-central-1%2Fs3%2Faws4_request&X-Amz-Signature=da85c6fe8a542ae3c171addf12a0c70417c6a8896d9074d782bfdabe063ba130)
Raw data about velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal VDE/mean VDE ratio could help in early high grade gliomas (HGG) diagnosis
Interval of consecutive MRI | VDE Pt #1 FLAIR | VDE Pt #2 FLAIR | VDE Pt #2 EN | VDE Pt #3 FLAIR | VDE Pt #3 EN | VDE Pt #4 FLAIR | VDE Pt #4 EN | Mean Values |
---|---|---|---|---|---|---|---|---|
35.50 | 169.23 | 311.81 | 16.68 | 0.00 | 11.93 | 16.81 | ||
17.03 | 258.82 | 104.54 | 6.66 | 0.00 | 0.00 | 10.81 | ||
32.24 | -52.97 | -94.91 | 43.39 | 64.14 | 0.00 | 0.00 | ||
64.59 | 47.84 | |||||||
155.18 | 165.74 | |||||||
0.00 | 48.53 | |||||||
28.26 | 125.03 | 107.15 | 47.75 | 54.37 | 3.98 | 9.21 | ||
125.63 | 135.36 | 324.99 | 300.00 | 221.49 | ||||
291.02 | 304.81 | 182.57 | 259.47 | |||||
240.48 |
Data on fluid attenuated inversion recovery (FLAIR) tumor and enhancing nodule (EN) volume velocity of diameter expansion (VDE). Reported as mm/year
Data about patient #1, #2, #3, #4
Raw data of mean acceleration (Acc) based on velocity of diameter expansion (VDE) of fluid attenuated inversion recovery (FLAIR) and enhancing nodule (EN) volume. Mean percentage maximal Acc/mean Acc ratio of each patient could help in early high grade gliomas (HGG) diagnosis
Interval of consecutive MRI | Acc Pt #1 FLAIR | Acc Pt #2 FLAIR | Acc Pt #2 EN | Acc Pt #3 FLAIR | Acc Pt #3 EN | Acc Pt #4 FLAIR | Acc Pt #4 EN | Mean Values |
---|---|---|---|---|---|---|---|---|
0.0003 | 0.0662 | 0.1220 | 0.00010 | 0 | 0.0002 | 0.0003 | ||
0.0005 | 0.0394 | 0.0159 | 0.00007 | 0 | 0.0000 | 0.0008 | ||
0.0015 | -0.0040 | -0.0072 | 0.00248 | 0.0037 | 0.0000 | 0.0000 | ||
0.00843 | 0.0062 | |||||||
0.03037 | 0.0324 | |||||||
0.00000 | 0.0046 | |||||||
0.0008 | 0.0339 | 0.0436 | 0.0069 | 0.0078 | 0.0001 | 0.0004 | ||
195.6695 | 195.5808 | 439.7477 | 300 | 282.7495 | ||||
280.0617 | 414.7516 | 77.74935 | 257.5209 | |||||
270.1352 |
Subpleural fibrotic interstitial lung abnormalities are implicated in non-small cell lung cancer radiotherapy outcomes The influence of BCL2, BAX, and ABCB1 gene expression on prognosis of adult de novo acute myeloid leukemia with normal karyotype patients CD56-positive diffuse large B-cell lymphoma: comprehensive analysis of clinical, pathological, and molecular characteristics with literature review Awake craniotomy for operative treatment of brain gliomas – experience from University Medical Centre Ljubljana