Combined Fluorescence-Guided Resection and Intracavitary Thermotherapy with Superparamagnetic Iron-Oxide Nanoparticles for Recurrent High-Grade Glioma: Case Series with Emphasis on Complication Management.

BACKGROUND: Concepts improving local tumor control in high-grade glioma (HGG) are desperately needed. The aim of this study is to report an extended series of cases treated with a combination of 5-ALA-fluorescence-guided resection (FGR) and intracavitary thermotherapy with superparamagnetic iron oxide nanoparticles (SPION). METHODS: We conducted a single-center retrospective review of all recurrent HGG treated with FGR and intracavitary thermotherapy (n = 18). Patients underwent six hyperthermia sessions in an alternating magnetic field and received additional adjuvant therapies on a case-by-case basis. RESULTS: Nine patients were treated for first tumor recurrence; all other patients had suffered at least two recurrences. Nine patients received combined radiotherapy and thermotherapy. The median progression-free survival was 5.5 (95% CI: 4.67-6.13) months and median overall survival was 9.5 (95% CI: 7.12-11.79) months. No major side effects were observed during active treatment. Thirteen patients (72%) developed cerebral edema and more clinical symptoms during follow-up and were initially treated with dexamethasone. Six (33%) of these patients underwent surgical removal of nanoparticles due to refractory edema. CONCLUSIONS: The combination of FGR and intracavitary thermotherapy with SPION provides a new treatment option for improving local tumor control in recurrent HGG. The development of cerebral edema is a major issue requiring further refinements of the treatment protocol.

Combined intracavitary thermotherapy with iron oxide nanoparticles and radiotherapy as local treatment modality in recurrent glioblastoma patients.

BACKGROUND: There is an increasing interest in local tumor ablative treatment modalities that induce immunogenic cell death and the generation of antitumor immune responses. METHODS: We report six recurrent glioblastoma patients who were treated with intracavitary thermotherapy after coating the resection cavity wall with superparamagnetic iron oxide nanoparticles ("NanoPaste" technique). Patients underwent six 1-h hyperthermia sessions in an alternating magnetic field and, if possible, received concurrent fractionated radiotherapy at a dose of 39.6 Gy. RESULTS: There were no major side effects during active treatment. However, after 2-5 months, patients developed increasing clinical symptoms. CT scans showed tumor flare reactions with prominent edema around nanoparticle deposits. Patients were treated with dexamethasone and, if necessary, underwent re-surgery to remove nanoparticles. Histopathology revealed sustained necrosis directly adjacent to aggregated nanoparticles without evidence for tumor activity. Immunohistochemistry showed upregulation of Caspase-3 and heat shock protein 70, prominent infiltration of macrophages with ingested nanoparticles and CD3+ T-cells. Flow cytometric analysis of freshly prepared tumor cell suspensions revealed increased intracellular ratios of IFN-γ to IL-4 in CD4+ and CD8+ memory T cells, and activation of tumor-associated myeloid cells and microglia with upregulation of HLA-DR and PD-L1. Two patients had long-lasting treatment responses > 23 months without receiving any further therapy. CONCLUSION: Intracavitary thermotherapy combined with radiotherapy can induce a prominent inflammatory reaction around the resection cavity which might trigger potent antitumor immune responses possibly leading to long-term stabilization of recurrent GBM patients. These results warrant further investigations in a prospective phase-I trial.

Multimodal Imaging of Patients With Gliomas Confirms 11C-MET PET as a Complementary Marker to MRI for Noninvasive Tumor Grading and Intraindividual Follow-Up After Therapy.

The value of combined L-( methyl-[11C]) methionine positron-emitting tomography (MET-PET) and magnetic resonance imaging (MRI) with regard to tumor extent, entity prediction, and therapy effects in clinical routine in patients with suspicion of a brain tumor was investigated. In n = 65 patients with histologically verified brain lesions n = 70 MET-PET and MRI (T1-weighted gadolinium-enhanced [T1w-Gd] and fluid-attenuated inversion recovery or T2-weighted [FLAIR/T2w]) examinations were performed. The computer software "visualization and analysis framework volume rendering engine (Voreen)" was used for analysis of extent and intersection of tumor compartments. Binary logistic regression models were developed to differentiate between World Health Organization (WHO) tumor types/grades. Tumor sizes as defined by thresholding based on tumor-to-background ratios were significantly different as determined by MET-PET (21.6 ± 36.8 cm3), T1w-Gd-MRI (3.9 ± 7.8 cm3), and FLAIR/T2-MRI (64.8 ± 60.4 cm3; P < .001). The MET-PET visualized tumor activity where MRI parameters were negative: PET positive tumor volume without Gd enhancement was 19.8 ± 35.0 cm3 and without changes in FLAIR/T2 10.3 ± 25.7 cm3. FLAIR/T2-MRI visualized greatest tumor extent with differences to MET-PET being greater in posttherapy (64.6 ± 62.7 cm3) than in newly diagnosed patients (20.5 ± 52.6 cm3). The binary logistic regression model differentiated between WHO tumor types (fibrillary astrocytoma II n = 10 from other gliomas n = 16) with an accuracy of 80.8% in patients at primary diagnosis. Combined PET and MRI improve the evaluation of tumor activity, extent, type/grade prediction, and therapy-induced changes in patients with glioma and serve information highly relevant for diagnosis and management.

Endoscopic management of a low-grade thalamic glioma: a safe alternative to open microsurgery?

BACKGROUND: Despite considerable advances in preoperative and intraoperative imaging and neuronavigation, resection of thalamic gliomas remains challenging. Although both endoscopic biopsy and third ventriculostomy (ETV) for the treatment of secondary hydrocephalus are commonly performed, endoscopic resection of thalamic gliomas has been very sparsely described. METHOD: We report and illustrate the surgical procedure and patient's outcome after full endoscopic resection of a thalamic glioma and to discuss this approach as an alternative to open microsurgery. RESULTS: In 2016, a 56-year-old woman presented with disorientation, dysphasia and right facial hypaesthesia in our department. Cranial magnetic resonance imaging revealed a left thalamic lesion and subsequent hydrocephalus. Initially, hydrocephalus was treated by ETV but forceps biopsy was not diagnostic. However, metabolism in 18F-fluoroethyl-L-tyrosine positron emission tomography indicated glioma. Subsequently, endoscopic and neuronavigation-guided tumour resection was performed using a <1 cm2, trans-sulcal approach through the left posterior horn of the lateral ventricle. While visibility was poor using the intraoperative microscope, neuroendoscopy provided excellent visualisation and allowed safe tumour debulking. Neither haemorrhage from the tumour or collapse of the cavity compromised endoscopic resection. CONCLUSIONS: In accordance with one previously published case of endoscopic resection of a thalamic glioma, no surgery-related complications were observed. Although this remains to be determined in larger series, endoscopic resection of these lesions might be a safe and feasible alternative to biopsy or open surgery. Future studies should also aim to identify patients specifically eligible for these approaches.

Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study.

OBJECT Delayed ischemic neurological deficits (DINDs) and cerebral vasospasm (CVS) are responsible fora poor outcome in patients with aneurysmal subarachnoid hemorrhage (SAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation. In this study, the authors examined the effects of treatment with the NO donor molsidomine with regard to decreasing the incidence of spasm-related delayed brain infarctions and improving clinical outcome in patients with SAH. METHODS Seventy-four patients with spontaneous aneurysmal SAH were included in this post hoc analysis. Twenty-nine patients with SAH and proven CVS received molsidomine in addition to oral or intravenous nimodipine. Control groups consisted of 25 SAH patients with proven vasospasm and 20 SAH patients without. These patients received nimodipine therapy alone. Cranial computed tomography (CCT) before and after treatment was analyzed for CVS-related infarcts. A modified National Institutes of Health Stroke Scale (mNIHSS) and the modified Rankin Scale (mRS) were used to assess outcomes at a 3-month clinical follow-up. RESULTS Four of the 29 (13.8%) patients receiving molsidomine plus nimodipine and 22 of the 45 (48%) patients receiving nimodipine therapy alone developed vasospasm-associated brain infarcts (p < 0.01). Follow-up revealed a median mNIHSS score of 3.0 and a median mRS score of 2.5 in the molsidomine group compared with scores of 11.5 and 5.0, respectively, in the nimodipine group with CVS (p < 0.001). One patient in the molsidomine treatment group died, and 12 patients in the standard care group died (p < 0.01). CONCLUSIONS In this post hoc analysis, patients with CVS who were treated with intravenous molsidomine had a significant improvement in clinical outcome and less cerebral infarction. Molsidomine offers a promising therapeutic option in patients with severe SAH and CVS and should be assessed in a prospective study.

Rationale of hyperbaric oxygenation in cerebral vascular insult.

Cerebrovascular diseases and especially ischemic stroke are a leading cause of death. They occur mostly due to an insufficient oxygen (O2) supply to the central neural tissue as a result of thromboembolic events and/or obstructive vessel disease. The primary damage of the brain tissue cannot be restored. However, adequate therapy could minimize secondary impairment of brain tissue and restore neuronal function in the so-called "penumbra region". Apart from reopening occluded vessels, additional O2 supply is essential for survival of malfunctioning neural tissue. Breathing of 100% O2 under hyperbaric conditions, hyperbaric oxygenation (HBO), is the only method to increase the O2 concentration in tissue with impaired blood supply. Experimental as well as clinical studies have reported a positive effect of HBO therapy. Survival rate has increased under HBO therapy and neurological outcome has improved. The optimal levels of pressure as well as duration and numbers of HBO sessions need to be specified to avoid undesirable effects. Unfortunately, many questions remain unanswered before routinely recommending HBO as additional therapy in clinical practice. In this review we consider the (patho-)physiological background of HBO-therapy, the latest results of experimental and clinical studies and stress the evidence in patients with cerebrovascular disease.