Evaluation of Resection Margin after Image-Guided Dural Tail Resection in Convexity Meningiomas.

Infiltration of adjacent dura with meningioma cells is a common phenomenon. Wide resection of the dural tail (DT) to achieve a gross total resection is a general recommendation. We aimed to investigate a tumor cell infiltration of the DT after image-guided resection of convexity meningiomas. The study's inclusion criteria were the diagnosis of convexity meningioma, planned Simpson I° resection, and an identifiable DT. Intraoperative image-guidance was applied to identify the outer edge of the DT and to guide resection. After resection, en-bloc specimen or four samples of outermost pieces of DT in case of piecemeal resection were sent for histological analysis. In addition to resection margin infiltration, the radiological extent of DT, radiomic characteristics (109 in total), histology, and demographic data were assessed. Hierarchical clustering was used to generate patient clusters for radiomic analysis. Twenty-two patients were included in the study, while 20 (91%) were female. The mean age was 54.2 (Standard deviation (SD) 13.9, range 30-85) years. En-bloc resection could be achieved in 4 patients. The remaining patients received piecemeal resection. 2 DT samples were omitted due to tumor infiltration of the superior sagittal sinus. None of the en-bloc resection samples demonstrated dural infiltration on the resection margin. Tumor cells were detected in 4 of 70 (5.7%) dural tail samples and could not be excluded in another 5 of 70 (7.1%). No tumor recurrences were detected at follow-up MRI examinations after a mean follow-up of 27.5 (SD 13.2, range 0 to 50.0) months. There was no significant association between DT infiltration and histological subtype or patient characteristics and between DT extent and tumor infiltration. Clustering according to radiomic characteristics was not associated with tumor infiltration (p = 0.89). The radiological dural tail does not reliably outline the extent of tumor cell infiltration in convexity meningiomas. Hence, the extent of dural tail resection should not exclusively be guided by preoperative radiological appearance.

Systematic Analysis of Combined Thrombolysis Using Ultrasound and Different Fibrinolytic Drugs in an in Vitro Clot Model of Intracerebral Hemorrhage.

Adequate removal of blood clots by minimally invasive surgery seems to correlate with a better clinical outcome in patients with intracerebral hemorrhages (ICHs). Moreover, neurotoxic effects of recombinant tissue plasminogen activator have been reported. The aim of this study was to improve fibrinolysis using an intra-clot ultrasound application with tenecteplase and urokinase in our established ICH clot model. One hundred thirty clots were produced from 25 or 50 mL of human blood, incubated for different periods and equipped with drainage, through which an ultrasound catheter was placed in 65 treatment clots for 1 h, randomly allocated into three groups: administration of ultrasound, administration of 60 IU of tenecteplase or administration of 30,000 IU urokinase. Relative end weights were compared. This study found a significant increase in thrombolysis caused by a combination of ultrasound and fibrinolytic drugs, whereas ultrasound and tenecteplase are significantly more effective in the treatment of larger and aged clots.

Radiomics of high-resolution computed tomography for the differentiation between cholesteatoma and middle ear inflammation: effects of post-reconstruction methods in a dual-center study.

OBJECTIVES: To evaluate the performance of radiomic features extracted from high-resolution computed tomography (HRCT) for the differentiation between cholesteatoma and middle ear inflammation (MEI), and to investigate the impact of post-reconstruction harmonization and data resampling. METHODS: One hundred patients were included in this retrospective dual-center study: 48 with histology-proven cholesteatoma (center A: 23; center B: 25) and 52 with MEI (A: 27; B: 25). Radiomic features (co-occurrence and run-length matrix, absolute gradient, autoregressive model, Haar wavelet transform) were extracted from manually defined 2D-ROIs. The ten best features for lesion differentiation were selected using probability of error and average correlation coefficients. A multi-layer perceptron feed-forward artificial neural network (MLP-ANN) was used for radiomics-based classification, with histopathology serving as the reference standard (70% of cases for training, 30% for validation). The analysis was performed five times each on (a) unmodified data and on data that were (b) resampled to the same matrix size, and (c) corrected for acquisition protocol differences using ComBat harmonization. RESULTS: Using unmodified data, the MLP-ANN classification yielded an overall median area under the receiver operating characteristic curve (AUC) of 0.78 (0.72-0.84). Using original data from center A and resampled data from center B, an overall median AUC of 0.88 (0.82-0.99) was yielded, while using ComBat harmonized data, an overall median AUC of 0.89 (0.79-0.92) was revealed. CONCLUSION: Radiomic features extracted from HRCT differentiate between cholesteatoma and MEI. When using multi-centric data obtained with differences in CT acquisition parameters, data resampling and ComBat post-reconstruction harmonization clearly improve radiomics-based lesion classification. KEY POINTS: • Unenhanced high-resolution CT coupled with radiomics analysis may be useful for the differentiation between cholesteatoma and middle ear inflammation. • Pooling of data extracted from inhomogeneous CT datasets does not appear meaningful without further post-processing. • When using multi-centric CT data obtained with differences in acquisition parameters, post-reconstruction harmonization and data resampling clearly improve radiomics-based soft-tissue differentiation.

Distant Metastases in Patients with Intrahepatic Cholangiocarcinoma: Does Location Matter? A Retrospective Analysis of 370 Patients.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive tumor entity, and distant metastases are common. However, studies investigating patterns and clinical relevance of distant metastases are rare. Therefore, we aimed to analyze occurrence, location, and prognostic impact of distant metastases on overall survival (OS). METHODS: Between 1997 and 2018, 417 patients with ICC were treated at our tertiary care center. Distant metastases and intrahepatic tumor burden were retrospectively evaluated in a longitudinal approach using volumetric assessment of cross-sectional imaging studies and all available medical/histopathological reports. RESULTS: Finally, 370 patients with histopathologically confirmed ICC were included. Of these, 186 showed distant metastases, either initially (n = 59) or during follow-up (n = 127). The most common metastatic sites were the lung (n = 105), peritoneum (n = 81), and bone (n = 50). After detection of lung metastases, the residual median OS was 5.3 months; followed by peritoneal metastases, 4.5 months, and bone metastases, 4.4 months (P=0.17). At the time of first metastatic occurrence, residual OS according to intrahepatic tumor burden of <25%, 25-50%, and >50% was 6.5 months, 4.9 months, and 1.2 months, respectively (P < 0.001). In multivariate hazard regression, hepatic tumor burden, liver function, and subsequent treatment were significant predictors of survival. CONCLUSIONS: During the disease course, every second patient developed extrahepatic metastases. While the presence of distant metastases was associated with poor patient outcomes, there was no significant difference between metastatic sites. However, hepatic tumor burden was the life-limiting risk factor in a majority of patients at the time of distant metastatic disease.

Risk Stratification in Advanced Biliary Tract Cancer: Validation of the A.L.A.N. Score.

BACKGROUND: In addition to the clinical parameters, immune-inflammatory markers have emerged as prognostic factors in patients with advanced biliary tract cancer (ABC). The recently proposed A.L.A.N. score combines both in an easily applicable manner. The aim of this study was to perform the first external evaluation of this score. METHODS: All patients from our clinical registry unit who had unresectable ABC underwent first-line chemotherapy from 2006 to 2018 and met the inclusion criteria of the original study were included (n = 74). The A.L.A.N. score comprises the following parameters: actual neutrophil count, lymphocyte-to-monocyte ratio, albumin, and neutrophil-to-lymphocyte ratio (A.L.A.N.). Univariate and multivariate hazard regression analyses were performed to evaluate the score's parameters regarding overall survival (OS). The concordance index (C-index) and integrated Brier score (IBS) were calculated to evaluate the score's predictive performance. RESULTS: Low, intermediate, and high A.L.A.N. scores corresponded to median OS of 21.9, 11.4, and 4.3 months, respectively, resulting in a significant risk stratification (log-rank p=0.017). In multivariate analysis, a high-risk A.L.A.N. score remained an independent predictor of poor survival (p=0.016). Neutrophil-to-lymphocyte ratio was not a significant factor for poor OS in the analyses in the cohort. The score's ability to predict individual patient survival was only moderate with a C-index of 0.63. CONCLUSIONS: The A.L.A.N. score can be used to identify risk groups with a poor prognosis prior to the start of chemotherapy. However, the ability of the score to predict individual patient outcome was only moderate; thus, it may only serve as a minor component in the complex interdisciplinary discussion.

Survival prediction for patients with non-resectable intrahepatic cholangiocarcinoma undergoing chemotherapy: a retrospective analysis comparing the tumor marker CA 19-9 with cross-sectional imaging.

PURPOSE: Carbohydrate antigen (CA) 19-9 has been established as the main serum marker for patients with intrahepatic cholangiocarcinoma (ICC). The aim of this study was to compare the prognostic value of CA 19-9 changes versus response determined by imaging in patients with ICC undergoing chemotherapy. METHODS: Between 2003 and 2018, 151 patients with histopathologically confirmed ICC underwent chemotherapy at our tertiary care center for non-resectable or recurrent ICC, of whom 121 were included in this study. Serum CA 19-9 levels and imaging were retrospectively evaluated during chemotherapy. Log-rank testing and optimal stratification were used to classify patients into risk groups. RESULTS: Prior to chemotherapy, baseline serum CA 19-9 levels above the previously published cut-off of 37 U/ml were associated with poor survival (median OS 8.7 vs. 12.4 months, p = 0.003). After the beginning of chemotherapy, an increase in CA 19-9 of more than 40 U/ml resulted in impaired residual survival (median OS 5.0 vs. 12.1 months, p < 0.001). However, progressive disease at the first follow-up imaging proved the strongest predictor for poor outcome (median OS 4.6 vs. 15.5 months, p < 0.001). In contrast to prior studies, our data did not show statistically relevant differences in survival time with respect to absolute or relative decreases in serum CA 19-9 levels. CONCLUSION: In our study, the disease control rate-that is, the absence of progressive disease-was the strongest predictor of prolonged residual OS. To this end, both CA 19-9 changes and progressive disease on initial follow-up showed remarkable discriminatory power, with the latter slightly outperforming the former. Therefore, imaging should remain the mainstay of patient evaluation during follow-up.

Multivariable non-invasive association of isocitrate dehydrogenase mutational status in World Health Organization grade II and III gliomas with advanced magnetic resonance imaging T2 mapping techniques.

AIM: To investigate multivariable analyses for noninvasive association of the isocitrate dehydrogenase (IDH) mutational status in grade II and III gliomas including evaluation of T2 mapping-sequences. METHODS: Magnetic resonance imaging (MRI) examinations with histopathologically proven World Health Organization grade II and III gliomas were retrospectively enrolled. Multivariate receiver operating characteristics (ROC) analyses to associate IDH mutational status were performed containing quantitative T2 mapping analyses and qualitative characteristics (sex, age, localization, heterogeneity, oedema, necrosis and diameter). Relaxation times were calculated pixelwise by means of standardized ROI analyses. Interobserver variability also was tested. RESULTS: Out of 32 patients (mean age: 50.7 years; range: 32-83), nine had grade II gliomas and 24 grade III, while 59.5% showed a positive IDH mutated state (IDHm) and 40.5% were wildtype (IDHw). Multivariable ROC analyses were calculated for relaxation time and range, localization and age with a cumulative 0.955 area under the curve (AUC) (p < 0.001), while central T2-relaxation time had by far the highest single variable sensitivity (AUC: 0.873; range: 0.762; age: 0.809; localization: 0.713). Age (cut off: 49 years; p = 0.031) and localization (p = 0.014) were the only qualitative parameters found to be significant as IDHw gliomas were older and IDHm gliomas were preferentially located fronto-temporal. CONCLUSIONS: This is the first study evaluating quantitative T2 mapping sequences for association of the IDH mutational status in grade II and III gliomas demonstrating an association between relaxation time and mutational status. Analyses of T2 mapping relaxation times may even be suitable for predicting the correct IDH mutational state. Prognostic accuracy increases significantly in predicting the correct mutational state when combing T2 relaxation time characteristics and the qualitative MRI features age and localization.

Longitudinal imaging and evaluation of SAH-associated cerebral large artery vasospasm in mice using micro-CT and angiography.

Longitudinal in vivo imaging studies characterizing subarachnoid hemorrhage (SAH)-induced large artery vasospasm (LAV) in mice are lacking. We developed a SAH-scoring system to assess SAH severity in mice using micro CT and longitudinally analysed LAV by intravenous digital subtraction angiography (i.v. DSA). Thirty female C57Bl/6J-mice (7 sham, 23 SAH) were implanted with central venous ports for repetitive contrast agent administration. SAH was induced by filament perforation. LAV was assessed up to 14 days after induction of SAH by i.v. DSA. SAH-score and neuroscore showed a highly significant positive correlation (rsp = 0.803, p < 0.001). SAH-score and survival showed a negative significant correlation (rsp = -0.71, p < 0.001). LAV peaked between days 3-5 and normalized on days 7-15. Most severe LAV was observed in the internal carotid (Δmax = 30.5%, p < 0.001), anterior cerebral (Δmax = 21.2%, p = 0.014), middle cerebral (Δmax = 28.16%, p < 0.001) and basilar artery (Δmax = 23.49%, p < 0.001). Cerebral perfusion on day 5 correlated negatively with survival time (rPe = -0.54, p = 0.04). Arterial diameter of the left MCA correlated negatively with cerebral perfusion on day 3 (rPe = -0.72, p = 0.005). In addition, pseudoaneurysms arising from the filament perforation site were visualized in three mice using i.v. DSA. Thus, micro-CT and DSA are valuable tools to assess SAH severity and to longitudinally monitor LAV in living mice.

Multiparametric 18F-FDG PET/MRI of the Breast: Are There Differences in Imaging Biomarkers of Contralateral Healthy Tissue Between Patients With and Without Breast Cancer?

The rationale was to assess whether there are differences in multiparametric 18F-FDG PET/MRI biomarkers of contralateral healthy breast tissue in patients with benign and malignant breast tumors. Methods: In this institutional review board-approved prospective single-institution study, 141 women with imaging abnormalities on mammography or sonography (BI-RADS 4/5) underwent combined 18F-FDG PET/MRI of the breast at 3T with dynamic contrast-enhanced MRI, diffusion-weighted imaging, and the radiotracer 18F-FDG. In all patients, the following imaging biomarkers were recorded for the contralateral (tumor-free) breast: breast parenchymal uptake (BPU) (from 18F-FDG PET), mean apparent diffusion coefficient (from diffusion-weighted imaging), background parenchymal enhancement (BPE), and amount of fibroglandular tissue (FGT) (from MRI). Appropriate statistical tests were used to assess differences in 18F-FDG PET/MRI biomarkers between patients with benign and malignant lesions. Results: There were 100 malignant and 41 benign lesions. BPE was minimal in 61 patients, mild in 56, moderate in 19, and marked in 5. BPE differed significantly (P < 0.001) between patients with benign and malignant lesions, with patients with cancer demonstrating decreased BPE in the contralateral tumor-free breast. FGT approached but did not reach significance (P = 0.055). BPU was 1.5 for patients with minimal BPE, 1.9 for mild BPE, 2.2 for moderate BPE, and 1.9 for marked BPE. BPU differed significantly between patients with benign lesions (mean, 1.9) and patients with malignant lesions (mean, 1.8) (P < 0.001). Mean apparent diffusion coefficient did not differ between groups (P = 0.19). Conclusion: Differences in multiparametric 18F-FDG PET/MRI biomarkers, obtained from contralateral tumor-free breast tissue, exist between patients with benign and patients with malignant breast tumors. Contralateral BPE, BPU, and FGT are decreased in breast cancer patients and may potentially serve as imaging biomarkers for the presence of malignancy.

Radiation-induced vascular changes in the intracranial irradiation field in medulloblastoma survivors: An MRI study.

BACKGROUND AND PURPOSE: While survival times after treatment of medulloblastoma are increasing, little is known about radiochemotherapy (RCT)-induced cerebrovascular changes. High resolution vessel wall imaging (VWI) sequences are an emerging tool for the evaluation of cerebrovascular diseases. We performed VWI in medulloblastoma long-term survivors to screen for late sequelae of RCT. MATERIAL AND METHODS: Twenty-two pediatric medulloblastoma survivors (mean age 25.8 years (10-53 years); 16.3 years (mean) post primary RCT (range 1-45 years)) underwent 2D VWI-MRI. Vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. The findings were correlated with the patients' radiation protocols. RESULTS: Vessel wall changes were observed the intracranial internal carotid artery (ICA) and the vertebrobasilar circulation (VBC) in 14 of 22 patients (63.6%). In multivariate analysis, time after RCT (OR = 1.38, p < 0.05) was strongest independent predictor for development of vessel wall alterations. The dose of radiation was not a relevant predictor. CONCLUSIONS: With longer follow-up time intracranial vessel wall changes are observed more frequently in medulloblastoma survivors. Thus VWI is a useful tool to monitor vessel wall alterations of cranially irradiated patients, creating the prerequisite for further treatment of late sequelae.

Evaluation of the apparent diffusion coefficient in patients with recurrent glioblastoma under treatment with bevacizumab with radiographic pseudoresponse.

BACKGROUND: Response Assessment in Neuro-Oncology Criteria (RANO), are used to asses response to first-line treatment of glioblastoma (GBM). Differentiation between response and pseudoresponse under treatment with Bevacizumab (BVZ) remains challenging. This study evaluates ADC changes in patients with radiographic pseudoresponse under treatment with (BVZ). METHODS: Patients (n=40) with recurrent GBM under-treatment with BVZ underwent MRI before, two and four months after treatment with BVZ. In patients with radiological pseudoresponse (n=11), ADC analyses were performed. Areas with decreasing T1 contrast enhancement (CE) and FLAIR signal decrease were manually selected and compared to size and position matched healthy contralateral brain parenchyma. RESULTS: Histogram based ADC (10-6×mm2/s) of these patients decreased significantly (P<0.005) from baseline MRI (T1-CE, FLAIR: 1124.9±160.3, 1098.4±226.2, respectively) to 2months (781.3±110.7, 783.3±103.3) and remained stable during 4months (777.0±138.5, 784.4±155.4, all mean±1 SD), despite progressive disease. Mean ADC values of the healthy contralateral brain tissue remained stable (P>0.05) (ADC values: baseline: 786.2±110.7, 2months: 781.1±76.2, 4months: 804.1±86.2). CONCLUSION: Treatment of GBM with BVZ leads to a decrease of ADC values in areas of pre-treatment T1-CE/FLAIR signal hyperintensity to levels of comparable with normal brain tissue. ADC values remained stable, even when progressive tumor growth was reported.

Susceptibility-weighted magnetic resonance imaging of cerebrovascular sequelae after radiotherapy for pediatric brain tumors.

BACKGROUND AND PURPOSE: Due to sensitive neuroimaging techniques, cerebrovascular complications such as cerebral microbleeds (CMB) and cerebral cavernous malformations (CCM) are increasingly recognized as considerable late effects after treatment for pediatric brain tumor. The aim of this study was to analyze CMB in a cohort of patients after cranial irradiation therapy for medulloblastoma or other pediatric brain tumors using susceptibility-weighted magnetic resonance imaging (SWI). MATERIALS AND METHODS: Forty former pediatric brain tumor patients were enrolled in this prospective cross-sectional study and examined by cranial MRI including SWI sequences. Cerebral microbleeds, clinical symptoms and disability were evaluated. RESULTS: Thirty-six (90%) of the examined individuals (mean follow-up age 22.2 y; mean follow-up time 13.5 y) were affected by CMB. Longer follow-up time and higher craniospinal irradiation doses correlated with higher total lesion count (p < 0.01). Thirteen patients (32.5%) presented with clinical symptoms. Individuals with CMB were more severely disabled than patients without CMB (p < 0.05). CONCLUSIONS: Cerebrovascular sequelae occur frequently after treatment for pediatric brain tumor. In this study, a remarkable part of pediatric brain tumor patients presents with CMB. As a sign of vascular damage, they can cause clinical symptoms and may correspond to neurocognitive decline. Further studies are needed to standardize MRI protocols and to improve quality of long-term follow-up.

Vessel shape alterations of the vertebrobasilar arteries in Mucopolysaccharidosis type IVa (Morquio A) patients.

PURPOSE: Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before. MATERIAL AND METHODS: MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS. RESULTS: The deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p<0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p<0.005). CONCLUSION: MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.

Novel loss of function mutation in KRIT1/CCM1 is associated with distinctly progressive cerebral and spinal cavernous malformations after radiochemotherapy for intracranial malignant germ cell tumor.

PURPOSE: Cerebrospinal cavernous malformations (CCMs) are vascular lesions characterized by dilated and leaky capillary caverns. CCMs can cause seizures, focal neurological deficits or acute intracranial hemorrhage; however, most patients are asymptomatic. CCMs occur either sporadically or as a familial autosomal-dominant disorder. We present a clinical and molecular study of a patient with distinctive cerebral and spinal cavernous malformations following radiochemotherapy for a malignant brain tumor. METHODS: The patient had multiple magnet resonance imaging (MRI) examinations of his brain and spine following radiochemotherapy for a primary intracranial germ cell tumor (GCT), as part of his oncologic follow-up. The MRI sequences included susceptibility-weighted imaging (SWI). The coding exons and their flanking intronic regions of KRIT1/CCM1 gene were analyzed for mutations by polymerase chain reaction (PCR) and direct sequencing. RESULTS: MRI revealed numerous cerebral and spinal microhemorrhages and pronounced cavernous malformations that progressed with subsequent follow-up imaging. Genetic analysis demonstrated a novel heterozygous KRIT1/CCM1 two base pair deletion (c.1535_1536delTG) in exon 14. This deletion leads to a frameshift with a premature stop codon at nucleotide position 1553 and a highly likely loss of function of the KRIT1 protein. CONCLUSION: We describe a patient with a novel heterozygous germ line loss of function mutation in KRIT1, which is associated with rapid-onset and highly progressive CCMs after radiochemotherapy for a malignant brain tumor.

Ischemic stroke and intracranial hemorrhage in patients with recurrent glioblastoma multiforme, treated with bevacizumab.

Bevacizumab (BVZ), a monoclonal antibody directed against vascular endothelial growth factor (VEGF), has been suspected to increase the incidence of ischemic stroke (IS) and intracranial hemorrhage (ICH) in GBM patients. Intracranial vascular events, such as IS and ICH, were retrospectively analyzed in 364 MRI scans of 82 patients with recurrent GBM (1st/2nd/3rd relapse). Out of these 82 patients, 40 were treated with BVZ (178 scans) in addition to basic treatment, whereas 42 patients matching for age and gender received basic treatment (186 scans). Distribution of typical vascular risk factors between both groups was analyzed retrospectively. In seven out of 82 patients (8%) vascular events were detected in MRI. Four vascular events were recorded in the BVZ-group (3 IS and 1 ICH), and 3 vascular events were found in the Control-group (1 IS and 2 ICH; p > 0.05 between both groups). Likewise, vascular risk factors (arterial hypertension, diabetes mellitus, obesity, former vascular event, hyperlipidemia, tobacco consumption and/or hypercholesterolemia) did not differ significantly between both groups. BVZ treatment does not seem to be associated with an increased risk for vascular events in patients with GBM in recurrence.