Molecular imaging and advanced MRI findings following immunotherapy in patients with brain tumors

Introduction: Currently, immunotherapy using vaccination strategies or oncolytic virus approaches, cell-based immunotherapy, and the blockade of immune checkpoints are under evaluation in patients with brain cancer. Here we summarize clinically significant imaging findings such as treatment-related changes detected by advanced neuroimaging techniques following the most suitable immunotherapy options currently used in neuro-oncology. We, furthermore, provide an overview of how these advanced imaging techniques may help to overcome shortcomings of standard MRI in the assessment and follow-up of patients with brain cancer. Areas covered: The current literature on neuroimaging for immunotherapy in the field of brain tumors, with a focus on gliomas and brain metastases is summarized. Expert commentary: Data suggest that imaging parameters primarily derived from amino acid PET, diffusion- and perfusion-weighted MRI, or MR spectroscopy are particularly helpful for the evaluation of treatment response and provide valuable information for the differentiation of treatment-induced changes from actual brain tumor progression following various immunotherapy approaches

Leptomeningeal Carcinomatosis in a Patient with Pancreatic Cancer Responding to Nab-Paclitaxel plus Gemcitabine

Leptomeningeal carcinomatosis is an extremely rare, but devastating complication in pancreatic cancer patients with a poor prognosis despite multimodal treatment. We present a 51-year-old male patient with the very rare condition of leptomeningeal carcinomatosis originating from pancreatic cancer. He presented to our hospital with severe headache and neck stiffness 30 months after systemic chemotherapy. Cerebral and spinal MRI as well as cerebrospinal fluid examination confirmed the diagnosis of leptomeningeal carcinomatosis. The patient responded to gemcitabine plus nab-paclitaxel in terms of elimination of tumor cells from the CSF and concurrent clinical improvement for 3 months. The observed findings suggest that the combination of gemcitabine plus nab-paclitaxel is potentially effective in affected cerebrospinal fluid of pancreatic carcinoma patients

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation

Novel therapeutic targets in malignant glioma patients are urgently needed. Point mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene occur predominantly in melanoma patients, but may also occur in gliomas. Thus, this is a target of great interest for this group of patients. In a nine-year-old male patient, an anaplastic astrocytoma in the left temporoparietal region was diagnosed histologically. After first-and second-line treatment, a malignant progression to a secondary glioblastoma was observed ten years after the initial diagnosis. Within the following seven years, all other conventional treatment options were exhausted. At this time point, recurrent tumor histology revealed an epithelioid glioblastoma, without a mutation in the isocitrate dehydrogenase gene (IDH wild-type). In order to identify a potential target for an experimental salvage therapy, mutational tumor analysis showed a BRAF V600E mutation. Consecutively, dabrafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images (MRI) were consistent with Stable Disease according to the Response Assessment in Neuro-Oncology Working Group (RANO) criteria for the following ten months until tumor progression was detected. The patient died 16 months after dabrafenib treatment initiation. Particularly in younger glioma patients as well as in patients with an epithelioid glioblastoma, screening for a V600E BRAF mutation is promising since, in these cases, targeted therapy with BRAF inhibitors seems to be a useful salvage treatment option

Clinical applications and prospects of PET imaging in patients with IDH-mutant gliomas

PET imaging using radiolabeled amino acids in addition to MRI has become a valuable diagnostic tool in the clinical management of patients with brain tumors. This review provides a comprehensive overview of PET studies in glioma patients with a mutation in the isocitrate dehydrogenase gene (IDH). A considerable fraction of these tumors typically show no contrast enhancement on MRI, especially when classified as grade 2 according to the World Health Organization classification of Central Nervous System tumors. Major diagnostic challenges in this situation are differential diagnosis, target definition for diagnostic biopsies, delineation of glioma extent for treatment planning, differentiation of treatment-related changes from tumor progression, and the evaluation of response to alkylating agents. The main focus of this review is the role of amino acid PET in this setting. Furthermore, in light of clinical trials using IDH inhibitors targeting the mutated IDH enzyme for treating patients with IDH-mutant gliomas, we also aim to give an outlook on PET probes specifically targeting the IDH mutation, which appear potentially helpful for response assessment

Clinical applications and prospects of PET imaging in patients with IDH-mutant gliomas

PET imaging using radiolabeled amino acids in addition to MRI has become a valuable diagnostic tool in the clinical management of patients with brain tumors. This review provides a comprehensive overview of PET studies in glioma patients with a mutation in the isocitrate dehydrogenase gene (IDH). A considerable fraction of these tumors typically show no contrast enhancement on MRI, especially when classified as grade 2 according to the World Health Organization classification of Central Nervous System tumors. Major diagnostic challenges in this situation are differential diagnosis, target definition for diagnostic biopsies, delineation of glioma extent for treatment planning, differentiation of treatment-related changes from tumor progression, and the evaluation of response to alkylating agents. The main focus of this review is the role of amino acid PET in this setting. Furthermore, in light of clinical trials using IDH inhibitors targeting the mutated IDH enzyme for treating patients with IDH-mutant gliomas, we also aim to give an outlook on PET probes specifically targeting the IDH mutation, which appear potentially helpful for response assessment

O-(2-18F-fluoroethyl)-L-tyrosine PET for evaluation of brain metastasis recurrence after radiotherapy: an effectiveness and cost-effectiveness analysis

Background. Conventional MRI is the standard method to diagnose recurrence of brain metastases after radiation. However, following radiation therapy, reactive transient blood-brain barrier alterations with consecutive contrast enhancement can mimic brain metastasis recurrence. Recent studies have suggested that O-(2-F-18-fluoroethyl)-Ltyrosine (FET) PET improves the correct differentiation of brain metastasis recurrence from radiation injury. Based on published evidence and clinical expert opinion, we analyzed effectiveness and cost-effectiveness of the use of FET PET in addition to MRI compared with MRI alone for the diagnosis of recurrent brain metastases. Methods. A decision-tree model was designed to compare the 2 diagnostic strategies from the perspective of the German Statutory Health Insurance (SHI) system. Effectiveness was defined as correct diagnosis of recurrent brain metastasis and was compared between FET PET with MRI and MRI alone. Costs were calculated for a baseline scenario and for a more expensive scenario. Robustness of the results was tested using sensitivity analyses. Results. Compared with MRI alone, FET PET in combination with MRI increases the rate of correct diagnoses by 42% (number needed to diagnose of 3) with an incremental cost-effectiveness ratio of is an element of 2821 (baseline scenario) and is an element of 4014 (more expensive scenario) per correct diagnosis. The sensitivity analyses confirmed the robustness of the results. Conclusions. The model suggests that the additional use of FET PET with conventional MRI for the diagnosis of recurrent brain metastases may be cost-effective. Integration of FET PET has the potential to avoid overtreatment with corresponding costs as well as unnecessary side effects

Automated Brain Tumor Detection and Segmentation for Treatment Response Assessment Using Amino Acid PET.

Evaluation of metabolic tumor volume (MTV) changes using amino acid PET has become an important tool for response assessment in brain tumor patients. MTV is usually determined by manual or semiautomatic delineation, which is laborious and may be prone to intra- and interobserver variability. The goal of our study was to develop a method for automated MTV segmentation and to evaluate its performance for response assessment in patients with gliomas. Methods: In total, 699 amino acid PET scans using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) from 555 brain tumor patients at initial diagnosis or during follow-up were retrospectively evaluated (mainly glioma patients, 76%). 18F-FET PET MTVs were segmented semiautomatically by experienced readers. An artificial neural network (no new U-Net) was configured on 476 scans from 399 patients, and the network performance was evaluated on a test dataset including 223 scans from 156 patients. Surface and volumetric Dice similarity coefficients (DSCs) were used to evaluate segmentation quality. Finally, the network was applied to a recently published 18F-FET PET study on response assessment in glioblastoma patients treated with adjuvant temozolomide chemotherapy for a fully automated response assessment in comparison to an experienced physician. Results: In the test dataset, 92% of lesions with increased uptake (n = 189) and 85% of lesions with iso- or hypometabolic uptake (n = 33) were correctly identified (F1 score, 92%). Single lesions with a contiguous uptake had the highest DSC, followed by lesions with heterogeneous, noncontiguous uptake and multifocal lesions (surface DSC: 0.96, 0.93, and 0.81 respectively; volume DSC: 0.83, 0.77, and 0.67, respectively). Change in MTV, as detected by the automated segmentation, was a significant determinant of disease-free and overall survival, in agreement with the physician's assessment. Conclusion: Our deep learning-based 18F-FET PET segmentation allows reliable, robust, and fully automated evaluation of MTV in brain tumor patients and demonstrates clinical value for automated response assessment

Differentiation of treatment-related changes from tumour progression: a direct comparison between dynamic FET PET and ADC values obtained from DWI MRI

BackgroundFollowing brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumour progression.Patients and methodsForty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment was 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI coregistered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach.ResultsTen of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89 ± 0.05; P < 0.001) than that of ADC values (threshold ADC, 1.09 × 10−3 mm2/s; accuracy, 69%; AUC, 0.73 ± 0.09; P = 0.13). The addition of static FET PET parameters to ADC values increased the latter’s accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). Moreover, in contrast to ADC values, TBRs <1.95 at suspected progression predicted a significantly longer survival (P = 0.01).ConclusionsData suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumour progression and outperform ADC measurement for this highly relevant clinical question

Differentiation of treatment-related changes from tumour progression: a direct comparison between dynamic FET PET and ADC values obtained from DWI MRI

BackgroundFollowing brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumour progression.Patients and methodsForty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment was 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI coregistered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach.ResultsTen of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89 ± 0.05; P < 0.001) than that of ADC values (threshold ADC, 1.09 × 10−3 mm2/s; accuracy, 69%; AUC, 0.73 ± 0.09; P = 0.13). The addition of static FET PET parameters to ADC values increased the latter’s accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). Moreover, in contrast to ADC values, TBRs <1.95 at suspected progression predicted a significantly longer survival (P = 0.01).ConclusionsData suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumour progression and outperform ADC measurement for this highly relevant clinical question

FET PET reveals considerable spatial differences in tumour burden compared to conventional MRI in newly diagnosed glioblastoma

PurposeAreas of contrast enhancement (CE) on MRI are usually the target for resection or radiotherapy target volume definition in glioblastomas. However, the solid tumour mass may extend beyond areas of CE. Amino acid PET can detect parts of the tumour that show no CE. We systematically investigated tumour volumes delineated by amino acid PET and MRI in patients with newly diagnosed, untreated glioblastoma.MethodsPreoperatively, 50 patients with neuropathologically confirmed glioblastoma underwent O-(2-[F-18]-fluoroethyl)-l-tyrosine (FET) PET, and fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced MRI. Areas of CE were manually segmented. FET PET tumour volumes were segmented using a tumour-to-brain ratio of 1.6. The percentage overlap volumes, and Dice and Jaccard spatial similarity coefficients (DSC, JSC) were calculated. FLAIR images were evaluated visually.ResultsIn 43 patients (86%), the FET tumour volume was significantly larger than the CE volume (21.514.3mL vs. 9.4 +/- 11.3mL; P<0.001). Forty patients (80%) showed both increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET uptake and CE was low (mean DSC 0.39 +/- 0.21, mean JSC 0.26 +/- 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In five patients (10%), increased FET uptake was present outside areas of FLAIR hyperintensity.ConclusionOur results show that the metabolically active tumour volume delineated by FET PET is significantly larger than tumour volume delineated by CE. Furthermore, the results strongly suggest that the information derived from both imaging modalities should be integrated into the management of patients with newly diagnosed glioblastoma