Radiomic features define risk and are linked to DNA methylation attributes in primary CNS lymphoma.

Background: The prognostic roles of clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma, but these approaches do not fully explain the observed variation in outcome. To date, neuroimaging or molecular information is not used. The aim of this study was to determine the utility of radiomic features to capture clinically relevant phenotypes, and to link those to molecular profiles for enhanced risk stratification. Methods: In this retrospective study, we investigated 133 patients across 9 sites in Austria (2005-2018) and an external validation site in South Korea (44 patients, 2013-2016). We used T1-weighted contrast-enhanced MRI and an L1-norm regularized Cox proportional hazard model to derive a radiomic risk score. We integrated radiomic features with DNA methylation profiles using machine learning-based prediction, and validated the most relevant biological associations in tissues and cell lines. Results: The radiomic risk score, consisting of 20 mostly textural features, was a strong and independent predictor of survival (multivariate hazard ratio = 6.56 [3.64-11.81]) that remained valid in the external validation cohort. Radiomic features captured gene regulatory differences such as in BCL6 binding activity, which was put forth as testable treatment target for a subset of patients. Conclusions: The radiomic risk score was a robust and complementary predictor of survival and reflected characteristics in underlying DNA methylation patterns. Leveraging imaging phenotypes to assess risk and inform epigenetic treatment targets provides a concept on which to advance prognostic modeling and precision therapy for this aggressive cancer.

Somatostatin receptor subtype expression and radiomics from DWI-MRI represent SUV of [68Ga]Ga-DOTATOC PET in patients with meningioma.

OBJECTIVE: This retrospective study aimed to analyse the correlation between somatostatin receptor subtypes (SSTR 1-5) and maximum standardized uptake value (SUVmax) in meningioma patients using Gallium-68 DOTA-D-Phe1-Tyr3-octreotide Positron Emission Tomography ([68Ga]Ga-DOTATOC PET). Secondly, we developed a radiomic model based on apparent diffusion coefficient (ADC) maps derived from diffusion weighted magnetic resonance images (DWI MRI) to reproduce SUVmax. METHOD: The study included 51 patients who underwent MRI and [68Ga]Ga-DOTATOC PET before meningioma surgery. SUVmax values were quantified from PET images and tumour areas were segmented on post-contrast T1-weighted MRI and mapped to ADC maps. A total of 1940 radiomic features were extracted from the tumour area on each ADC map. A random forest regression model was trained to predict SUVmax and the model's performance was evaluated using repeated nested cross-validation. The expression of SSTR subtypes was quantified in 18 surgical specimens and compared to SUVmax values. RESULTS: The random forest regression model successfully predicted SUVmax values with a significant correlation observed in all 100 repeats (p < 0.05). The mean Pearson's r was 0.42 ± 0.07 SD, and the root mean square error (RMSE) was 28.46 ± 0.16. SSTR subtypes 2A, 2B, and 5 showed significant correlations with SUVmax values (p < 0.001, R2 = 0.669; p = 0.001, R2 = 0.393; and p = 0.012, R2 = 0.235, respectively). CONCLUSION: SSTR subtypes 2A, 2B, and 5 correlated significantly with SUVmax in meningioma patients. The developed radiomic model based on ADC maps effectively reproduces SUVmax using [68Ga]Ga-DOTATOC PET.

ADC textural features in patients with single brain metastases improve clinical risk models.

AIMS: In this retrospective study we performed a quantitative textural analysis of apparant diffusion coefficient (ADC) images derived from diffusion weighted MRI (DW-MRI) of single brain metastases (BM) patients from different primary tumors and tested whether these imaging parameters may improve established clinical risk models. METHODS: We identified 87 patients with single BM who had a DW-MRI at initial diagnosis. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences, hyperintense T2 lesions (peritumoral border zone (T2PZ)) and tumor-free gray and white matter compartment (GMWMC) were generated and registered to corresponding ADC maps. ADC textural parameters were generated and a linear backward regression model was applied selecting imaging features in association with survival. A cox proportional hazard model with backward regression was fitted for the clinical prognostic models (diagnosis-specific graded prognostic assessment score (DS-GPA) and the recursive partitioning analysis (RPA)) including these imaging features. RESULTS: Thirty ADC textural parameters were generated and linear backward regression identified eight independent imaging parameters which in combination predicted survival. Five ADC texture features derived from T2PZ, the volume of the T2PZ, the normalized mean ADC of the GMWMC as well as the mean ADC slope of T2PZ. A cox backward regression including the DS-GPA, RPA and these eight parameters identified two MRI features which improved the two risk scores (HR = 1.14 [1.05;1.24] for normalized mean ADC GMWMC and HR = 0.87 [0.77;0.97]) for ADC 3D kurtosis of the T2PZ.) CONCLUSIONS: Textural analysis of ADC maps in patients with single brain metastases improved established clinical risk models. These findings may aid to better understand the pathogenesis of BM and may allow selection of patients for new treatment options.

Phosphorous Magnetic Resonance Spectroscopy and Molecular Markers in IDH1 Wild Type Glioblastoma.

The World Health Organisation's (WHO) classification of brain tumors requires consideration of both histological appearance and molecular characteristics. Possible differences in brain energy metabolism could be important in designing future therapeutic strategies. Forty-three patients with primary, isocitrate dehydrogenase 1 (IDH1) wild type glioblastomas (GBMs) were included in this study. Pre-operative standard MRI was obtained with additional phosphorous magnetic resonance spectroscopy (31-P-MRS) imaging. Following microsurgical resection of the tumors, biopsy specimens underwent neuropathological diagnostics including standard molecular diagnosis. The spectroscopy results were correlated with epidermal growth factor (EGFR) and O6-Methylguanine-DNA methyltransferase (MGMT) status. EGFR amplified tumors had significantly lower phosphocreatine (PCr) to adenosine triphosphate (ATP)-PCr/ATP and PCr to inorganic phosphate (Pi)-PCr/Pi ratios, and higher Pi/ATP and phosphomonoesters (PME) to phosphodiesters (PDE)-PME/PDE ratio than those without the amplification. Patients with MGMT-methylated tumors had significantly higher cerebral magnesium (Mg) values and PME/PDE ratio, while their PCr/ATP and PCr/Pi ratios were lower than in patients without the methylation. In survival analysis, not-EGFR-amplified, MGMT-methylated GBMs showed the longest survival. This group had lower PCr/Pi ratio when compared to MGMT-methylated, EGFR-amplified group. PCr/Pi ratio was lower also when compared to the MGMT-unmethylated, EGFR not-amplified group, while PCr/ATP ratio was lower than all other examined groups. Differences in energy metabolism in various molecular subtypes of wild-type-GBMs could be important information in future precision medicine approach.

Perampanel in brain tumor and SMART-syndrome related epilepsy - A single institutional experience.

Epilepsy is common in patients with brain tumors and frequently presents as the first clinical manifestation of an underlying tumor. Despite a number of available antiepileptic drugs (AED), brain tumor related epilepsy (BTRE) may still be difficult to control. Recently, the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptor antagonist perampanel (PER) is increasingly acknowledged as an attractive novel add-on AED for seizure control in BTRE. We present a single institutional experience reporting five individual cases with refractory BTRE treated with PER. In two of these five brain tumor patients, worsening of seizure control was caused by SMART-syndrome (stroke-like migraine attacks after radiation therapy). Efficacy of PER was assessed by the responder rate and by evaluating overall changes in seizure frequency before and during PER treatment. In our case series, a reduction in seizure frequency was observed in four out of five patients and the responder rate was 40%. In addition, both cases with symptomatic epilepsy associated with SMART-syndrome were successfully treated with PER. This case series supports the growing evidence that PER may become a promising add-on AED for the treatment of refractory BTRE as well as for seizure control in SMART-syndrome.

Epileptic Activity Increases Cerebral Amino Acid Transport Assessed by 18F-Fluoroethyl-l-Tyrosine Amino Acid PET: A Potential Brain Tumor Mimic.

O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET is a well-established method increasingly used for diagnosis, treatment planning, and monitoring in gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings. Whether seizures also affect 18F-FET PET imaging is currently unknown. The aim of this retrospective analysis was to investigate the brain amino acid metabolism during epileptic seizures by 18F-FET PET and to elucidate the pathophysiologic background. METHODS: Ten patients with 11 episodes of serial seizures or status epilepticus, who underwent MRI and 18F-FET PET, were studied. The main diagnosis was glioma World Health Organization grade II-IV (n = 8); 2 patients suffered from nonneoplastic diseases. Immunohistochemical assessment of LAT1/LAT2/CD98 amino acid transporters was performed in seizure-affected cortex (n = 2) and compared with glioma tissues (n = 3). RESULTS: All patients exhibited increased seizure-associated strict gyral 18F-FET uptake, which was reversible in follow-up studies or negative shortly before and without any histologic or clinical signs of tumor recurrence. 18F-FET uptake corresponded to structural MRI changes, compatible with cortical vasogenic and cytotoxic edema, partial contrast enhancement, and hyperperfusion. Patients with prolonged postictal symptoms lasting up to 8 wk displayed intensive and widespread (≥ 1 lobe) cortical 18F-FET uptake. LAT1/LAT2/CD98 was strongly expressed in neurons and endothelium of seizure-affected brains and less in reactive astrocytosis. CONCLUSION: Seizure activity, in particular status epilepticus, increases cerebral amino acid transport with a strict gyral 18F-FET uptake pattern. Such periictal pseudoprogression represents a potential pitfall of 18F-FET PET and may mimic brain tumor. Our data also indicate a seizure-induced upregulation of neuronal, endothelial, and less astroglial LAT1/LAT2/CD98 amino acid transporter expression.

Targeted Therapies for the Treatment of Brain Metastases in Solid Tumors.

Brain metastases are a major cause of morbidity and mortality in cancer patients. While the mainstay treatment comprises surgery and radiation therapy, the role of systemic agents remains controversial. In general, it has been presumed that poor blood-brain barrier (BBB) penetration and inherently more resistant metastatic brain disease preclude a favorable systemic treatment approach. However, a better understanding of tumor biology and the subsequent development of targeted drugs have reawakened interest in systemic therapy. Despite still limited brain distribution, a variety of targeted drugs have demonstrated activity in brain metastases in early clinical trials. Nevertheless, disease progression commonly occurs, and it remains to be elucidated whether limited CNS drug distribution or the acquisition of resistant metastatic clones must be held responsible for this prognosis. Moreover, micrometastatic brain disease beyond an intact BBB-and ultimately prevention of brain metastasis formation-may generally remain inaccessible for first-generation targeted agents with poor CNS penetration. To overcome limited brain distribution and possibly emerging acquired resistance, highly potent next-generation targeted drugs with enhanced CNS distribution have been developed. In view of this emerging but yet undefined role of targeted therapies in the treatment of brain metastases from solid tumors, this review aims to summarize the current knowledge from clinical trials and discusses clinically relevant obstacles to overcome.

Progressive multifocal leukoencephalopathy complicating untreated chronic lymphatic leukemia: case report and review of the literature.

A 58-year old female with a four-year history of previously untreated CLL at Binet stage A complained about word finding problems, impaired vision, and gait unsteadiness. Concerning her CLL she was asymptomatic and had never required any specific treatment. Her neurological examination disclosed cognitive alterations, homonyme hemianopia to the right, aphasia, and mild right-sided hemiparesis. Cerebral MRI showed a hyperintense lesion on T2 weighted images without contrast enhancement. CSF examination revealed normal findings, including CSF protein, cell count, cytology and PCR-analysis was negative for the presence of JC virus DNA. On follow-up MRI, performed 2 weeks later, the T2 lesion was further enlarging. Subsequent stereotactic brain biopsy was diagnostic for PML revealing abnormal oligodendrocytes staining positive against antibodies specific for simian vacuolating virus 40. In addition, repeated CSF analyses for JC-Virus DNA in the course of the disease became positive. After confirmation of diagnosis treatment with mirtazapine (30 mg/d) and mefloquine (250 mg/d) was initiated. Rapid clinical progression correlated to further worsening on MRI. Therefore this treatment was terminated after 16 days and the regime was changed to a five-day courses of cytarabine (2 mg/kg/d) combined with intrathecal administration of liposomal cytarabine (50 mg). Due to further clinical progression with global aphasia, blindness and severe right-sided hemiparesia, medication was stopped. The Patient died three and a half months after onset of symptoms.

Polyarteritis nodosa complicating multiple myeloma - a case report and review of the literature.

INTRODUCTION: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to-medium-sized vessels, rarely associated with hematologic neoplasms. CASE REPORT: We report a 44-year-old man with a history of monoclonal gammopathy of undetermined significance (MGUS) who presented with rapidly progressing sensorimotor peripheral neuropathy. Two weeks after onset the patient developed severe acute acral and retinal ischemia. MR-angiography and nerve biopsy revealed a systemic necrotizing vasculitis (PAN type). At this time, bone marrow biopsy identified a smoldering multiple myeloma. Immediate immunosuppressive and anti-neoplastic treatment (steroids, immunoglobulins, bortezomib combined with cyclophosphamide followed by lenalidomide maintenance) resulted in a favorable clinical outcome. After 4 years, the patient is in good clinical condition with sustained partial remission from myeloma and without evidence of relapse of PAN. CONCLUSION: This is a remarkable case of a histologically confirmed peripheral neuropathy due to polyarteritis nodosa associated with progression of MGUS to multiple myeloma. Immediate diagnosis and combined immunosuppressive and anti-neoplastic treatment may improve the outcome of this potentially life-threatening clinical condition.

O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma.

UNLABELLED: The objective of this study was to compare MRI response assessment with metabolic O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET response evaluation during antiangiogenic treatment in patients with recurrent high-grade glioma (rHGG). METHODS: Eleven patients with rHGG were treated biweekly with bevacizumab-irinotecan. MR images and (18)F-FET PET scans were obtained at baseline and at follow-up 8-12 wk after treatment onset. MRI treatment response was evaluated by T1/T2 volumetry according to response assessment in neurooncology (RANO) criteria. For (18)F-FET PET evaluation, an uptake reduction of more than 45% calculated with a standardized uptake value of more than 1.6 was defined as a metabolic response (receiver-operating-characteristic curve analysis). MRI and (18)F-FET PET volumetry results and response assessment were compared with each other and in relation to progression-free survival (PFS) and overall survival (OS). RESULTS: At follow-up, MR images showed partial response in 7 of 11 patients (64%), stable disease in 2 of 11 patients (18%), and tumor progression in 2 of 11 patients (18%). In contrast, (18)F-FET PET revealed 5 of 11 metabolic responders (46%) and 6 of 11 nonresponders (54%). MRI and (18)F-FET PET showed that responders survived significantly longer than did nonresponders (10.24 vs. 4.1 mo, P = 0.025, and 7.9 vs. 2.3 mo, P = 0.015, respectively). In 4 patients (36.4%), diagnosis according to RANO criteria and (18)F-FET PET was discordant. In these cases, PET was able to detect tumor progression earlier than was MRI. CONCLUSION: In rHGG patients undergoing antiangiogenic treatment, (18)F-FET PET seems to be predictive for treatment failure in that it contributes important information to response assessment based solely on MRI and RANO criteria.

Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme.

PURPOSE: The receptor tyrosine kinase Axl has recently been identified as a critical element in the invasive properties of glioma cell lines. However, the effect of Axl and its ligand growth arrest--specific gene 6 (Gas6) in human gliomas is still unknown. EXPERIMENTAL DESIGN: Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffin-embedded glioma specimens by means of reverse transcription-PCR and immunohistochemistry. The prognostic value of Axl and Gas6 expression was evaluated using a population-based tissue microarray derived from a cohort of 55 glioblastoma multiforme (GBM) patients. RESULTS: Axl and Gas6 were detectable in gliomas of malignancy grades WHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 protein in 74% of GBM samples, respectively. GBM patients with high Axl expression and Axl/Gas6 coexpression showed a significantly shorter time to tumor progression and an association with poorer overall survival. Comparative immunohistochemical studies showed that Axl staining was most pronounced in glioma cells of pseudopalisades and reactive astrocytes. Additionally, Axl/Gas6 coexpression was observed in glioma cells and tumor vessels. In contrast, Axl staining was not detectable in nonneoplastic brain tissue and Gas6 was strongly expressed in neurons. CONCLUSIONS: In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Our results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment.

Molecular therapies for malignant glioma.

Due to the dismal prognosis of malignant glioma with currently available therapies there is an urgent need for new treatments based on a better molecular understanding of gliomagenesis. Several concepts of molecular therapies for malignant glioma are currently being studied in preclinical and clinical settings, including small molecules targeting specific receptor-mediated signaling pathways and gene therapy. Many growth factors, growth factor receptors--usually receptor tyrosine kinases--and receptor-associated signaling pathways are critically involved in gliomagenesis. Numerous selective inhibitors, which specifically block such molecules, are currently evaluated for clinical applicability. Several gene therapy approaches have shown antitumor efficacy in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. In clinical trials, retroviral herpes-simplex-thymidinkinase- (HSV-Tk-) gene therapy has been the pioneering and most commonly used approach. However, efficient gene delivery into the tumor cells still remains the crucial obstacle for successful clinical gene therapy. During the past few years a number of new gene transfer vectors based on adeno-, adeno-associated-, herpes- and lentiviruses as well as new carrier cell systems, including neural and endothelial progenitor cells, have been developed. In addition, antisense technologies have advanced in recent years and entered clinical testing utilizing intratumoral administration by convection-enhanced delivery, exemplified by ongoing clinical trials of intratumoral administration of antisense TGF-beta. This paper summarizes some of these recent developments in molecular therapies for malignant glioma, focusing on targeted therapies using selective small molecules and gene therapy concepts.

MALDI-TOF mass spectrometry analysis of cerebrospinal fluid tryptic peptide profiles to diagnose leptomeningeal metastases in patients with breast cancer.

Leptomeningeal metastasis (LM) is a devastating complication that occurs in 5% of patients with breast cancer. Early diagnosis and initiation of treatment are essential to prevent neurological deterioration. However, early diagnosis of LM remains challenging because 25% of cerebrospinal fluid (CSF) samples produce false-negative results at first cytological examination. We developed a new, MS-based method to investigate the protein expression patterns present in the CSF from patients with breast cancer with and without LM. CSF samples from 106 patients with active breast cancer (54 with LM and 52 without LM) and 45 control subjects were digested with trypsin. The resulting peptides were measured by MALDI-TOF MS. Then, the mass spectra were analyzed and compared between patient groups using newly developed bioinformatics tools. A total of 895 possible peak positions was detected, and 164 of these peaks discriminated between the patient groups (Kruskal-Wallis, p<0.01). The discriminatory masses were clustered, and a classifier was built to distinguish patients with breast cancer with and without LM. After bootstrap validation, the classifier had a maximum accuracy of 77% with a sensitivity of 79% and a specificity of 76%. Direct MALDI-TOF analysis of tryptic digests of CSF gives reproducible peptide profiles that can assist in diagnosing LM in patients with breast cancer. The same method can be used to develop diagnostic assays for other neurological disorders.

Low concentrations of STI571 in the cerebrospinal fluid: a case report.

We report a 53-year-old man with lymphoid blast crisis of Ph+ chronic myeloid leukaemia who was treated with STI571, a selective inhibitor of the enzymatic activity of BCR-ABL. He responded excellently to STI571 (600 mg/d), obtaining a complete cytogenetic remission after 3 months of therapy. Although remission in the bone marrow was sustained, the patient developed an isolated central nervous system relapse. Subsequent analyses of STI571 concentrations in the cerebrospinal fluid (CSF) revealed 2-log lower CSF levels of STI571 than corresponding plasma levels. These are the first data demonstrating a low penetration of orally administered STI571 into the CSF in humans.