Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up.

PURPOSE: Multimodal therapies have significantly improved prognosis in glioma. However, in particular radiotherapy may induce long-term neurotoxicity compromising patients' neurocognition and quality of life. The present prospective multicenter study aimed to evaluate associations of multimodal treatment with neurocognition with a particular focus on hippocampal irradiation. METHODS: Seventy-one glioma patients (WHO grade 1-4) were serially evaluated with neurocognitive testing and quality of life questionnaires. Prior to (baseline) and following further treatment (median 7.1 years [range 4.6-11.0] after baseline) a standardized computerized neurocognitive test battery (NeuroCog FX) was applied to gauge psychomotor speed and inhibition, verbal short-term memory, working memory, verbal and non-verbal memory as well as verbal fluency. Mean ipsilateral hippocampal radiation dose was determined in a subgroup of 27 patients who received radiotherapy according to radiotherapy plans to evaluate its association with neurocognition. RESULTS: Between baseline and follow-up mean performance in none of the cognitive domains significantly declined in any treatment modality (radiotherapy, chemotherapy, combined radio-chemotherapy, watchful-waiting), except for selective attention in patients receiving chemotherapy alone. Apart from one subtest (inhibition), mean ipsilateral hippocampal radiation dose > 50 Gy (Dmean) as compared to < 10 Gy showed no associations with long-term cognitive functioning. However, patients with Dmean < 10 Gy showed stable or improved performance in all cognitive domains, while patients with > 50 Gy numerically deteriorated in 4/8 domains. CONCLUSIONS: Multimodal glioma therapy seems to affect neurocognition less than generally assumed. Even patients with unilateral hippocampal irradiation with > 50 Gy showed no profound cognitive decline in this series.

Mid-term treatment-related cognitive sequelae in glioma patients.

PURPOSE: Cognitive functioning represents an essential determinant of quality of life. Since significant advances in neuro-oncological treatment have led to prolonged survival it is important to reliably identify possible treatment-related neurocognitive dysfunction in brain tumor patients. Therefore, the present study specifically evaluates the effects of standard treatment modalities on neurocognitive functions in glioma patients within two years after surgery. METHODS: Eighty-six patients with World Health Organization (WHO) grade 1-4 gliomas were treated between 2004 and 2012 and prospectively followed within the German Glioma Network. They received serial neuropsychological assessment of attention, memory and executive functions using the computer-based test battery NeuroCog FX. As the primary outcome the extent of change in cognitive performance over time was compared between patients who received radiotherapy, chemotherapy or combined radio-chemotherapy and patients without any adjuvant therapy. Additionally, the effect of irradiation and chemotherapy was assessed in subgroup analyses. Furthermore, the potential impact of the extent of tumor resection and histopathological characteristics on cognitive functioning were referred to as secondary outcomes. RESULTS: After a median of 16.8 (range 5.9-31.1) months between post-surgery baseline neuropsychological assessment and follow-up assessment, all treatment groups showed numerical and often even statistically significant improvement in all cognitive domains. The extent of change in cognitive functioning showed no difference between treatment groups. Concerning figural memory only, irradiated patients showed less improvement than non-irradiated patients (p = 0.029, η2 = 0.06). Resected patients, yet not patients with biopsy, showed improvement in all cognitive domains. Compared to patients with astrocytomas, patients with oligodendrogliomas revealed a greater potential to improve in attentional and executive functions. However, the heterogeneity of the patient group and the potentially selected cohort may confound results. CONCLUSION: Within a two-year post-surgery interval, radiotherapy, chemotherapy or their combination as standard treatment did not have a detrimental effect on cognitive functions in WHO grade 1-4 glioma patients. Cognitive performance in patients with adjuvant treatment was comparable to that of patients without.

The accuracy of clinical neck staging for p16-positive and negative oropharyngeal cancer and its therapeutic implications.

PURPOSE: Oropharyngeal squamous cell carcinoma (OPSCC) may be treated with primary surgery or primary (chemo)radiation. While surgery with concurrent neck dissection provides definitive pathological staging of the neck, non-surgical treatment relies on clinical staging for treatment planning. To assess the accuracy of clinical neck staging, we compared clinical to surgical staging after primary surgery in patients with p16-negative and p16-positive OPSCC. METHODS: Retrospective analysis of clinical, pathological, and oncologic outcome data of patients with OPSCC treated with primary surgery and bilateral neck dissection. Clinical and pathological nodal status were compared for p16-negative and p16-positive patients. Patients with occult metastatic disease were analyzed in detail. RESULTS: 95 patients were included. 60.5% of p16-negative patients and 66.6% of p16-positive patients had pathologically confirmed metastatic neck disease. p16-positive patients had improved 24-month recurrence-free survival compared to p16-negative patients at 93.3% vs. 69.6%. Pathological N-status differed from clinical N-status in 36.8% of p16-negative patients vs. 31.6% of p16-positive patients. Occult metastatic disease was more common in p16-negative patients at 18.4% vs. 8.8% for p16-positive patients. Clinical detection sensitivity for extranodal extension was low overall; sensitivity was 27.3% and specificity was 91.6% for p16-negative patients vs. 61.5% and 80.0% for p16-positive patients, respectively. CONCLUSION: Our data show a considerable degree of inaccuracy of clinical neck staging results in all OPSCC patients which needs to be taken into consideration during therapy planning. For p16-positive patients, these findings warrant attention in the context of therapy deintensification to avoid undertreatment.

Radiation exposure in the intra-arterial nimodipine therapy of subarachnoid hemorrhage related cerebral vasospasm.

The selective intra-arterial nimodipine application for the treatment of cerebral vasospasm (CVS) in patients after spontaneous subarachnoid hemorrhage (sSAH) is widely employed. The purpose of this study is to examine the radiation exposure and to determine local diagnostic reference levels (DRLs) of intra-arterial nimodipine therapy. In a retrospective study design, DRLs and achievable dose (AD) were assessed for all patients undergoing (I) selective intra-arterial nimodipine application or (II) additional mechanical angioplasty for CVS treatment. Interventional procedures were differentiated according to the type of procedure and the number of probed vessels. Altogether 494 neurointerventional procedures of 121 patients with CVS due to sSAH could be included. The radiation exposure indices were distributed as follows: (I) DRL 74.3 Gy·cm2, AD 59.8 Gy·cm2; (II) DRL 128.3 Gy·cm2, AD 94.5 Gy·cm2. Kruskal-Wallis test confirmed significant dose difference considering the number of probed vessels (p< 0.001). The mean cumulative dose per patient was 254.9 Gy·cm2(interquartile range 88.6-315.6 Gy·cm2). The DRLs of intra-arterial nimodipine therapy are substantially lower compared with DRLs proposed for other therapeutic interventions, such as thrombectomy or aneurysm coiling. However, repeated therapy sessions are often required, bearing the potential risk of a cumulatively higher radiation exposure.

Spot signs in intracerebral hemorrhage: useful for identifying patients at risk for hematoma enlargement?

BACKGROUND: Prognostic signs for the identification of patients with acute spontaneous intracerebral hemorrhage (SICH) prone to hematoma expansion are limited. Contrast extravasation (spot signs, SpS) on computed tomographic angiography (CTA) may be a promising method to predict hematoma expansion in acute SICH. However, prospective data on the predictive value of the SpS on hematoma expansion and clinical outcome are still limited. We aimed to investigate associations between the presence of SpS, hematoma expansion, and clinical outcome in acute SICH. METHODS: A prospective observational study was performed between 08/2008 and 08/2011. Patients with SICH presenting within 6 h of symptom onset were included. Patients with secondary hematomas, purely intraventricular hematomas, incomplete CT evaluation, hematoma evacuation prior to follow-up brain imaging, and incomplete follow-up data and those who refused to give consent for data analysis were excluded. CT and CTA brain imaging were carried out in all patients at baseline. After 24 h, follow-up brain imaging was performed. Hematoma location, hematoma volume, and substantial hematoma expansion were documented. CTA images were evaluated by two investigators for the presence of SpS. In all positive SpS cases, images were additionally reviewed by a third rater to achieve consensus for interpretating contrast extravasation. Clinical outcome was measured by the modified Rankin Scale (mRS) at discharge and at 3 months. RESULTS: In total, 101 patients [median age 73 years (interquartile range 60-79); male 61.4%] were included in the analysis. Median time from onset to CTA was 128 min (interquartile range 90-209 min); median initial National Institute of Health Stroke Scale score was 16 (8-21). SpS were detected in 27 patients (26.7%). Cohen's kappa for the presence of SpS was 0.606, indicating moderate agreement. SpS patients had significantly higher initial hematoma volumes than patients without SpS (36.0 vs. 14.39 ml, p = 0.005). Hematoma expansion was significantly more frequent in SpS patients (59.3 vs. 21.6%, p < 0.001) and associated with the presence of SpS in the univariate analysis (OR 5.273; 95% CI 2.047-13.584, p = 0.001) and in multivariable analysis adjusted for the initial hematoma volume (OR 4.678, 95% CI 1.781-12.288, p = 0.002). Sensitivity of SpS to predict hematoma expansion was 0.5, specificity was 0.84. The positive likelihood ratio for SpS to predict hematoma expansion was 3.136 (95% CI 1.649-5.967), the negative likelihood ratio was 0.595 (95% CI 0.414-0.854). No difference in 3-month clinical outcome was observed between patients with and without SpS (median mRS score 4 and 4, p = 0.457). CONCLUSIONS: The clinical value of SpS needs to be further explored. Future studies should particularly focus on structured training procedures to identify SpS and measure the time needed to precisely assess the presence of SpS and on the prevalence of SpS in consecutive intracerebral hemorrhage populations.

Bevacizumab does not increase the risk of remote relapse in malignant glioma.

Preclinical evidence and uncontrolled clinical studies suggest an increased risk for distant spread and development of a gliomatosislike phenotype at recurrence or progression of malignant glioma patients treated with bevacizumab (BEV), an antibody to vascular endothelial growth factor (VEGF). Here we asked whether BEV treatment of recurrent malignant glioma increases the risk of distant or diffuse tumor spread at further recurrence. BEV-treated patients were compared with matched pairs of patients treated without anti-VEGF regimens. T1 contrast-enhanced (T1+c) and fluid-attenuated inversion recovery (FLAIR) images were analyzed using a novel automated tool of image analysis. At the start of the study, 20.5% of BEV-treated and 22.7% of non-BEV-treated patients had displayed distant or diffuse recurrence. Distant or diffuse recurrences were observed in 22% (BEV) and 18% (non-BEV) on T1+c and in 25% and 18% on FLAIR (p > 0.05). The correlation between changes on T1+c and FLAIR at progression was high. The risk of distant or diffuse recurrence at the time of failure of BEV-containing treatments was not higher than with anti-VEGF-free regimens, arguing against a specific property of BEV that promotes distant tumor growth or a gliomatosislike phenotype at recurrence.

CT and DSA for evaluation of spontaneous intracerebral lobar bleedings.

Purpose: This study retrospectively examined the extent to which computed tomography angiography (CTA) and digital subtraction angiography (DSA) can help identify the cause of lobar intracerebral bleeding. Materials and methods: In the period from 2002 to 2020, data from patients who were >18 years at a university and an academic teaching hospital with lobar intracerebral bleeding were evaluated retrospectively. The CTA DSA data were reviewed separately by two neuroradiologists, and differences in opinion were resolved by consensus after discussion. A positive finding was defined as an underlying vascular etiology of lobar bleeding. Results: The data of 412 patients were retrospectively investigated. DSA detected a macrovascular cause of bleeding in 125/412 patients (33%). In total, sixty patients had AVMs (15%), 30 patients with aneurysms (7%), 12 patients with vasculitis (3%), and 23 patients with dural fistulas (6%). The sensitivity, specificity, positive and negative predictive values, and accuracy of CTA compared with DSA were 93, 97, 100, and 97%. There were false-negative CTA readings for two AVMs and one dural fistula. Conclusion: The DSA is still the gold standard diagnostic modality for detecting macrovascular causes of ICH; however, most patients with lobar ICH can be investigated first with CTA, and the cause of bleeding can be found. Our results showed higher sensitivity and specificity than those of other CTA studies.

Does age matter? - A MRI study on peritumoral edema in newly diagnosed primary glioblastoma.

BACKGROUND: Peritumoral edema is a characteristic feature of malignant glioma related to the extent of neovascularisation and to vascular endothelial growth factor (VEGF) expression.The extent of peritumoral edema and VEGF expression may be prognostic for patients with glioblastoma. As older age is a negative prognostic marker and as VEGF expression is reported to be increased in primary glioblastoma of older patients, age-related differences in the extent of peritumoral edema have been assessed. METHODS: In a retrospective, single-center study, preoperative magnetic resonance imaging (MRI) scans of steroid-naïve patients (n = 122) of all age groups were analysed. Patients with clinically suspected, radiologically likely or known evidence of secondary glioblastoma were not included.Extent of brain edema was determined in a metric quantitative fashion and in a categorical fashion in relation to tumor size. Analysis was done group-wise related to age. Additionally, tumor size, degree of necrosis, superficial or deep location of tumor and anatomic localization in the brain were recorded. RESULTS: The extent of peritumoral edema in patients >65 years (ys) was not different from the edema extent in patients ≤ 65 ys (p = 0.261). The same was true if age groups ≤ 55 ys and ≥ 70 ys were compared (p = 0.308). However, extent of necrosis (p = 0.023), deep tumor localization (p = 0.02) and frontal localisation (p = 0.016) of the tumor were associated with the extent of edema. Tumor size was not linearly correlated to edema extent (Pearson F = 0.094, p = 0.303) but correlated to degree of necrosis (F = 0.355, p < 0.001, Spearman-Rho) and depth of tumor (p < 0.001). In a multifactorial analysis of maximum edema with the uncorrelated factors age, regional location of tumor and degree of necrosis, only the extent of necrosis (p = 0.022) had a significant effect. CONCLUSION: Age at diagnosis does not determine degree of peritumoral edema, and tumor localization in the white matter is associated with greater extent of edema. The area of necrosis is reflective of volume of edema. In summary, the radiographic appearance of a glioblastoma at diagnosis does not reflect biology in the elderly patient.

Generating Virtual Short Tau Inversion Recovery (STIR) Images from T1- and T2-Weighted Images Using a Conditional Generative Adversarial Network in Spine Imaging.

Short tau inversion recovery (STIR) sequences are frequently used in magnetic resonance imaging (MRI) of the spine. However, STIR sequences require a significant amount of scanning time. The purpose of the present study was to generate virtual STIR (vSTIR) images from non-contrast, non-fat-suppressed T1- and T2-weighted images using a conditional generative adversarial network (cGAN). The training dataset comprised 612 studies from 514 patients, and the validation dataset comprised 141 studies from 133 patients. For validation, 100 original STIR and respective vSTIR series were presented to six senior radiologists (blinded for the STIR type) in independent A/B-testing sessions. Additionally, for 141 real or vSTIR sequences, the testers were required to produce a structured report of 15 different findings. In the A/B-test, most testers could not reliably identify the real STIR (mean error of tester 1-6: 41%; 44%; 58%; 48%; 39%; 45%). In the evaluation of the structured reports, vSTIR was equivalent to real STIR in 13 of 15 categories. In the category of the number of STIR hyperintense vertebral bodies (p = 0.08) and in the diagnosis of bone metastases (p = 0.055), the vSTIR was only slightly insignificantly equivalent. By virtually generating STIR images of diagnostic quality from T1- and T2-weighted images using a cGAN, one can shorten examination times and increase throughput.