Prognostic role and interaction of TERT promoter status, telomere length and MGMT promoter methylation in newly diagnosed IDH wild-type glioblastoma patients.

BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.

Metronomic Temozolomide in Heavily Pretreated Patients With Recurrent Isocitrate Dehydrogenase Wild-type Glioblastoma: A Large Real-Life Mono-Institutional Study.

AIMS: Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population. MATERIALS AND METHODS: All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification. RESULTS: In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0-2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1-7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3-6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3-2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3-3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3-0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3-07, P = 0.001) was the only factor associated with overall survival. The most common grade 3-4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%). CONCLUSIONS: Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.

Infraoptic course of the anterior cerebral artery associated with an anterior communicating artery aneurysm: anatomic case report and embryological considerations

OBJECTIVE AND IMPORTANCE: An infraoptic course of the proximal anterior cerebral artery is a rare anomaly that has been reported in 32 cases to date, often in association with cerebral aneurysms. This anomaly represents a maldevelopment in the embryogenesis of the anterior circle of Willis, resulting from the persistence of the primitive prechiasmal arterial anastomosis or an error in the development of the definitive ophthalmic artery (OphA). The case of a patient with a ruptured middle cerebral artery aneurysm and an anterior communicating artery aneurysm associated with this anomaly is described, and the anatomic features are outlined. CLINICAL PRESENTATION: A 30-year-old male patient with a right temporal hematoma and subarachnoid hemorrhage was admitted to our department 4 days after the hemorrhaging episode, with normal neurological examination results. Angiography revealed a right middle cerebral artery aneurysm and an anterior communicating artery aneurysm with an anomalous precommunicating tract. INTERVENTION: The patient was surgically treated 14 days after the hemorrhaging episode, through a right frontopterional craniotomy; both aneurysms were excluded by clipping. The anomalous infraoptic proximal tract of the anterior cerebral artery was well documented, with its origin adjacent to the OphA. The patient remained neurologically intact after surgery and was discharged 8 days later. CONCLUSION: The anomalous infraoptic course of the proximal anterior cerebral artery was associated with a low bifurcation of the ipsilateral internal carotid artery and the absence of the contralateral precommunicating tract in this patient. The strict anatomic relationship with the origin of the OphA suggests an error in the development of the definitive OphA, with persistence of an anastomotic loop between the primitive dorsal and ventral OphAs. It is concluded that, for aneurysm surgery, careful angiographic evaluation and an understanding of the neurovascular relationships in the circle of Willis are essential for a successful postoperative course, especially when very rare vascular anomalies are treated.

Hemodynamic effects of preoperative embolization in cerebral arteriovenous malformations: evaluation with transcranial Doppler sonography.

A series of 83 patients with cerebral arteriovenous malformations is presented. All patients were evaluated with transcranial Doppler sonography. Thirty-two patients were treated with staged embolization and surgery: 19 of these patients were operated on within 4 weeks of the last embolization, and the remaining 13 patients underwent surgery 6 months or more from embolization. Transcranial Doppler sonography performed 1 day after embolization showed a significant (> 60%) reduction of main feeder flow velocity in 72% of patients after the first embolization and in 45% of patients after the second embolization. In no case did such a significant reduction occur after the third embolization. A flow redistribution in the basal vessels (defined as an increase in flow velocity of at least 30% of the initial value) occurred only in patients after the first embolization (64%). On delayed post-embolization studies, complete recovery of flow velocity in the embolized vessel occurred in 46% of patients, and sonographic recruitment of new feeders occurred in the remaining 54%. When main feeder flow velocity (mean) was higher than 120 cm/s after embolization and before surgery, the incidence of postoperative hyperemic complications (cerebral edema and/or intracerebral hematoma) was significantly higher than in patients with a mean flow velocity under 120 cm/s. It is concluded that transcranial Doppler sonography is a valuable method for a noninvasive hemodynamic assessment of shunt flow in arteriovenous malformations, and it permits a physiological monitoring of hemodynamic changes after embolization and allows more precise indications regarding further stages of embolization and timing of surgery after embolization.

CO2 reactivity of cerebral vasospasm after aneurysmal subarachnoid haemorrhage.

CO2 reactivity of the brain vessels was investigated in 33 patients (Grade I-III after Hunt and Hess) with cerebral vasospasm after an aneurysmal subarachnoid haemorrhage (SAH) and after early operation within 72 hours. In all cases, transcranial Doppler sonography was used to measure flow velocities in the middle cerebral artery (MCA) and internal carotid artery (ICA) and vasomotor reactivity to CO2 changes. Vasospastic conditions lead to higher flow velocities through the narrow segment, lower peripheral stream resistance due to the post-stenotic pressure drop and lower vasodilating capacities of arterioles under hypercapnia. In severe vasospastic conditions, the peripheral stream bed is already maximally dilated and the hypercapnic response is weak. On the other hand, the peripheral vascular bed reacts normally to hypocapnia in all vasospastic situations. Our results point out two dangerous conditions of vasospastic disease: 1) exhaustion of peripheral vasodilating capacities, and 2) hyperventilatory therapy. Both of these situations can result in a reduction of CBF to brain tissue, mainly for two reasons: 1) In the former, a further increase in vasospasm cannot be compensated for anymore when the peripheral arterioles are maximally dilated, and 2) in the latter, hypocapnia produces a strong peripheral vasoconstrictor response with further reduction of CBF.