Functional Near-Infrared Spectroscopy to Probe State- and Trait-Like Conditions in Chronic Tinnitus: A Proof-of-Principle Study

Objective. Several neuroscience tools showed the involvement of auditory cortex in chronic tinnitus. In this proof-of-principle study we probed the capability of functional near-infrared spectroscopy (fNIRS) for the measurement of brain oxygenation in auditory cortex in dependence from chronic tinnitus and from intervention with transcranial magnetic stimulation. Methods. Twenty-three patients received continuous theta burst stimulation over the left primary auditory cortex in a randomized sham-controlled neuronavigated trial (verum = 12; placebo = 11). Before and after treatment, sound-evoked brain oxygenation in temporal areas was measured with fNIRS. Brain oxygenation was measured once in healthy controls (n = 12). Results. Sound-evoked activity in right temporal areas was increased in the patients in contrast to healthy controls. Left-sided temporal activity under the stimulated area changed over the course of the trial; high baseline oxygenation was reduced and vice versa. Conclusions. By demonstrating that rTMS interacts with auditory evoked brain activity, our results confirm earlier electrophysiological findings and indicate the sensitivity of fNIRS for detecting rTMS induced changes in brain activity. Moreover, our findings of trait-and state-related oxygenation changes indicate the potential of fNIRS for the investigation of tinnitus pathophysiology and treatment response

Bevacizumab and carboplatin increase survival and asymptomatic tumor volume in a glioma model

To evaluate efficacy and MRI findings after intravenous bevacizumab and/or carboplatin in a human glioma animal model, we randomized male nude rats with intracerebral UW28 human glioma xenografts to four groups: (1) controls (n = 9), (2) bevacizumab 10 mg/kg (n = 6), (3) carboplatin 200 mg/m2 (n = 6), and (4) bevacizumab + carboplatin (n = 6). MRI was performed on the day of treatment (day 7–10) and 1 week later, and rats were followed for survival. Dynamic MRI was done in three controls and three rats treated with bevacizumab with or without carboplatin before and 24 h after treatment. Median overall survival (OS) was as follows: group 1, 16 days; group 2, 23 days; group 3, 22 days; group 4, 36 days. OS was significantly longer in group 4 than in group 1 (p = 0.0011), group 2 (p = 0.0014), and group 3 (p = 0.0015), and rats had significantly larger tumors. No objective tumor responses were observed on MR images at 1 week after treatment; however, after bevacizumab, dynamic MRI showed reduced gadolinium enhancement intensity and increased time to peak, consistent with decreased vascular permeability. Carboplatin + bevacizumab is effective and superior over bevacizumab or carboplatin monotherapy in this animal model. Increased survival concomitant with increased asymptomatic tumor volume is suggestive that vascular targeting with reduced peritumoral edema and mass effect contributes to the efficacy of bevacizumab. The promising survival data warrant future clinical trials using bevacizumab + carboplatin

Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models1

Abstract The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX) on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally) 24 hours before human ovarian carcinoma (SKOV3), small cell lung carcinoma (LX-1 SCLC), and glioma (UW28, U87MG, and U251) tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0%) of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive) infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues

Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus

Purpose: Clinical effects of repetitive transcranial magnetic stimulation (rTMS) in chronic tinnitus are moderate. More precise coil localisation strategies, innovative stimulation protocols, and identification of predictors for treatment response were proposed as promising attempts to enhance treatment efficacy. In this pilot study we investigated neuronavigated continuous theta burst TMS (cTBS). Methods: Twenty-three patients received neuronavigated cTBS over the left primary auditory cortex in a randomized sham-controlled trial (verum = 12; sham = 11). Treatment response was evaluated with tinnitus questionnaires and numeric rating scales. Immediate change in numeric rating scales during the first session was used as predictor for treatment response. Results: Tinnitus was significantly reduced after treatment, but there were no superior effects between verum vs. sham treatment. Immediate change in the first treatment session predicted the response to treatment only in the verum group. Conclusions: In our study, verum cTBS was not superior to sham which highlights the persistent need for improving non-invasive brain stimulation techniques for the treatment of tinnitus. Future research should focus on the transfer of positive single session effects to daily treatment trials

Long-Term Outcomes of Intra-Arterial Chemotherapy for Progressive or Unresectable Pilocytic Astrocytomas: Case Studies.

BACKGROUND: Progressive and/or unresectable pilocytic astrocytomas (PAs) carry a poor prognosis compared to typical PA. Early radiotherapy (RT) may have severe long-term neurocognitive side effects in this patient population. Intra-arterial (IA) chemotherapy is a viable alternative or addition to intravenous (IV) chemotherapy, which may be beneficial in avoidance of early RT. OBJECTIVE: To evaluate the safety and efficacy of IA chemotherapy in this subset of patients. METHODS: This is a retrospective review of medical records of PA patients who are treated with IA chemotherapy at Oregon Health & Science University from 1997 until 2019. Response to treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Progression free survival (PFS) and overall survival (OS) are also reported. RESULTS: Twelve patients were identified. All patients experienced progression prior to initiation of IA chemotherapy. The most common grade 3 or 4 toxicities related to chemotherapy were thrombocytopenia (66%), neutropenia (66%), leukopenia (50%), anemia (33%), and lymphopenia (16%). Responses achieved were CR in 1, PR in 3, SD in 7, and PD in 1. Median PFS and median OS were 16.5 and 83.5 mo, respectively. A total of 112 procedures (IA injections) were performed and 250 arteries were catheterized. There were 3 minor and no major complications attributable to procedures. CONCLUSION: This study demonstrates that IA chemotherapy can be safely used in patients with unresectable or progressive PA

Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma

To determine the efficacy of methotrexate and/or rituximab in a CNS lymphoma model and to evaluate MRI modalities for monitoring efficacy, we inoculated female athymic nude rats (rnu/rnu) intracerebrally with human MC116 B-lymphoma cells. Between days 16 and 26, rats were randomized to receive intravenous (IV) treatment with (1) saline (controls, n = 15), (2) methotrexate 1,000 mg/m2 (n = 6), (3) rituximab 375 mg/m2 (n = 6), or (4) rituximab plus methotrexate (n = 6). T2/fluid-attenuated inversion recovery (FLAIR) and gadolinium contrast-enhanced T1 MRI sequences were performed prior to and 1 week after treatment. IV rituximab gave an objective tumor response in four of six animals (>50% reduction in tumor volume comparing pre- and posttreatment T2/FLAIR MRI) and resulted in stable disease (50%–125% of baseline) in another animal. The percent change in tumor volume on T2/FLAIR images was significantly different in the control versus rituximab group (p = 0.0051). IV methotrexate slowed tumor growth, compared to controls, but only one of six animals had an objective response. In untreated controls, tumor histological volumes correlated well with T2/FLAIR or contrast-enhanced T1 images (r = 0.877). In the treatment groups, T2/FLAIR correlation was good, but the gadolinium-enhanced T1 MRI was not significantly correlated with histology (r = 0.19). The MC116 CNS lymphoma model seems valuable for preclinical testing of efficacy and toxicity of treatment regimens. IV rituximab was highly effective, but methotrexate was only minimally effective. T2/FLAIR was superior to contrast-enhanced T1 for monitoring efficacy

Diagnosis of pseudoprogression using MRI perfusion in patients with glioblastoma multiforme may predict improved survival

AIMS: This retrospective study determined the survival of glioblastoma patients with or without pseudoprogression. METHODS: A total of 68 patients were included. Overall survival was compared between patients showing pseudoprogression (in most cases diagnosed using perfusion MRI with ferumoxytol) and in patients without pseudoprogession. MGMT methylation status was also analyzed in the pseudoprogression cases. RESULTS: Median survival in 24 (35.3%) patients with pseudoprogression was 34.7 months (95% CI: 20.3–54.1), and 13.4 months (95% CI: 11.1–19.5) in 44 (64.7%) patients without pseudoprogression (p < 0.0001). The longest survival was a median of 54.1 months in patients with combination of pseudoprogression and (MGMT) promoter methylation. CONCLUSION: Pseudoprogression is associated with better outcome, especially if concurring with MGMT promoter methylation. Patients never diagnosed with pseudoprogression had poor survival. This study emphasizes the importance of differentiating tumor progression and pseudoprogression using perfusion MRI