I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65210710.31857/S0044467724010051КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯResearch ArticleGlioblastoma phenotypic and genetic heterogeneity, comparison of MRI and PET/CT parameters with tumor molecular genetic characteristicsФенотипическая и генетическая гетерогенность глиобластом, сопоставление параметров МРТ и ПЭТ/КТ с молекулярно-генетическими характеристиками опухолиVikhrovaN. B.ВихроваН. Б.
Russian Federation
nvikhrova@nsi.ruKalaevaD. B.КалаеваД. Б.
Russian Federation
nvikhrova@nsi.ruBatalovA. I.БаталовА. И.
Russian Federation
nvikhrova@nsi.ruProninI. N.ПронинИ. Н.
Russian Federation
nvikhrova@nsi.ruBurdenko National Medical Research Center of Neurosurgery, Ministry of Healthcare of RussiaФГАУ “НМИЦ нейрохирургии им. академика Н. Н. Бурденко” Минздрава России10072024741485902022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/652107

Glioblastoma (GB) is an extremely heterogeneous tumor, which is caused by genomic instability, high growth rate, and neovascularization. Molecular and genetic characteristics of GB play a major role in the prognosis of the disease, which is reflected in the new WHO classification of CNS tumors from 2021.

Purpose of this research is comparison MRI parameters (ADC & CBF), metabolic activity on 11C-MET PET/СT with glioblastoma genetic profile. 40 patients (age 55±12 years, sex M/F = 31/9) with newly diagnosed GB were examined by MRI with assessment of diffusion parameters (ADCmin) and ASL perfusion (CBFmax) and 11С-МЕТ PET/CT with the calculation of tumor to normal index (METmax). Since these VOI (1cm3) did not always coincide, it was decided to measure all parameters in each VOI on all image maps (PMOD automatic contour transfer). A total of 9 measurements were obtained for each patient: METmax, METcbf, METadc; ADCmin, ADCmet, ADCcbf; CBFmax, CBFmet, CBFadc. Comparative and correlation analysis was carried out both in the total GB group and separately in the groups MGMT+/and EGFR+/and different Ki67 levels (cut-off 20%). In results 45% of patients had CBFmax, ADCmin and METmax mismatch. Significant correlations were found in the METmax VOI between METmax&ADCmet (Rs = -0.37) and METcbf&ADCcbf (Rs = -0.05). CBFmax and CBFmet correlated with Ki67 (Rs = 0.38 and Rs = 0.48, respectively) and increased in Ki67 > 20% GB group. GB genetic subgroup analysis showed: MGMT+ had significantly higher ADCmin>1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77, it means that cells were more tightly packed. In METmax VOI, METmax was negatively correlated with ADCmet (Rs = -0.72) and CBFmet was positively correlated with Ki-67 (Rs = 0.89); EGFR+ tumors had significantly higher METmax > 3.29 (Se = 88%, Sp = 70%, AUC = 0.82), that was negatively correlated with ADCmet (Rs = -0.85). In case when Ki67 > 20% GB demonstrated significantly higher CBFmax >108.177ml/100/min (Se = 70%, Sp = 94%, AUC 0.75) and a strong negative correlation between METmax and ADCmet, (Rs = -0,65) in METmax VOI. Our study shown that CBFmax, ADCmin and METmax localization coincide in 45% of cases, which proves the presence of variety in the structure and functional activity of different areas of GB. The correlation of MGMT methylation and ADC (ADCmin > 1.01 (10-3 mm2/sec), Se = 78%, Sp = 74%, AUC = 0.77) confirms the recent studies results of this tumor subtype lower needs of the new membranes construction, that’s due to the inhibition of the mechanism of the DNA repair system. EGFR amplification presence in our patient sample was associated with a significant higher MET metabolism (МЕTmax > 3.29, Se = 88%, Sp = 70%, AUC = 0.82) and correlated with height level of Ki67 (Rs = -0.85), confirming the fact of GB cells amino acids increased consumption for membrane synthesis. The obtained correlations MET with ADC and the absence of those with CBF, confirms the dependence glioma methionine metabolism of the new cell membranes building, rather than on neovascularization.

Revealed mismatch of MRI and PET/CT parameters confirmed GB structure heterogeneity phenomenon, as well as their significant differences in various genetic status GB subgroups.

Глиобластома (ГБ) отличается высокой степенью неоднородности развития в пространстве и времени, что вызвано геномной нестабильностью, высокой скоростью роста отдельных участков и гетерогенной неоваскуляризацией. Молекулярно-генетические особенности ГБ играют важную роль в прогнозе заболевания, что отражено в новой классификации ВОЗ опухолей ЦНС от 2021 г. Целью данного исследования стало сопоставление параметров кровотока и диффузии по данным МРТ, метаболизма опухолевой ткани по данным ПЭТ/КТ с генетическим профилем ГБ. 40 пациентам (возраст 55 ± 12 лет, пол М/Ж = 31/9) с впервые поставленным диагнозом ГБ проведена оценка параметров МРТ (измеряемого коэффициента диффузии – ADC, скорости кровотока – CBF –по данным ASL-перфузии) и ПЭТ/КТ в виде индекса накопления метионина (MET). Все вышеперечисленные объемные контуры (VOI – 1 см3) автоматически с помощью программного обеспечения (PMOD) были перенесены на все имеющиеся карты изображений и сопоставлены друг с другом; итого получено 9 параметров: METmax, METcbf, METadc, ADCmin, ADCmet, ADCcbf, CBFmax, CBFmet, CBFadc. Проведен сравнительный и корреляционный анализ параметров как в общей группе ГБ, так и отдельно в генетически разных подгруппах (MGMT+/и EGFR+/-) и по уровню Ki67.

Исследование показало, что локализации зон высоких значений кровотока, плотноклеточности и метаболизма аминокислот совпадают только в 45% случаев, доказывая наличие различий в структуре и функциональной активности участков ГБ. Данные о взаимосвязи метилирования промотора гена MGMT и ADC (ADCmin > 1.01 (10–3 мм2/с), Se = 78%, Sp = 74%, AUC = 0.77) подтверждают результаты других авторов о более низкой потребности данного генетического подтипа ГБ в строительстве новых мембран, обусловленной угнетением механизма системы репарации ДНК. Выявление амплификации гена EGFR в нашей выборке было ассоциировано со значимым повышением метаболизма МЕТ (МЕTmax > 3.29, Se = 88%, Sp = 70%, AUC = 0.82) и коррелировало с более высоким индексом Ki67 (Rs = –0.85), подтверждая факт увеличения потребления аминокислот клетками ГБ для синтеза мембран. Полученные корреляционные связи между ИН MET и ADC, отсутствие таковых с параметрами CBF подтверждают зависимость метаболизма метионина в глиомах от процессов построения новых клеточных мембран, а не от неоваскуляризации. Феномен гетерогенности структуры ГБ был подтвержден на основе выявленных различий в локализации зон максимальных значений изучаемых параметров МРТ и ПЭТ/КТ, а также их значимых отличий в группах ГБ с разным молекулярно-генетическим профилем.

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