Study protocol for a prospective, randomized, multicenter trial to investigate the influence of peripheral nerve stimulation on patients with chronic sacroiliac joint syndrome (SILENCING).

BACKGROUND: The prevalence of sacroiliac joint pain (SIJP) is estimated to be 10-30% in patients with chronic low back pain. Numerous conservative and surgical treatment modalities for SIJP have been described with limited evidence regarding long-term pain relief. Spinal cord stimulation (SCS) is a well-established technique to treat patients with chronic low back pain. However, the effect on patients with SIJP is not consistent. Therefore, peripheral nerve stimulation (PNS) for chronic SIJP was implemented in experimental trials. Clinical data on PNS for SIJP is still lacking. The authors present a case series and a protocol for a prospective, multicenter study to determine the effect of PNS in patients with chronic intractable SIJP. METHOD: A multicenter, prospective randomized controlled trial was designed. Patients with chronic intractable SIJP will be recruited and randomized in a 4:3 ratio to either the peripheral nerve stimulation group or to the best medical treatment group. A total of 90 patients are planned to be enrolled (52 in the PNS group and 38 in the BMT group). Patients in the intervention group receive a percutaneous implantation of a unilateral or bilateral lead which is externalized for a trial phase for 3-14 days. After trial phase only patients with at least 50% reduction of pain receive an impulse generator for permanent stimulation. Regular visits for participants are planned on day 0, after 3 months (± 30 days), 6 months (± 30 days), and 12 months (± 60 days). The primary outcome measurements is the difference in Numeric Pain Rating Scale (NRS) between baseline and after 6 months. Secondary outcomes is improvement of pain associated disability (ODI) and improvement of health-related quality of life after 6 and 12 months. DISCUSSION: We have described the protocol for a prospective, multicenter, randomized trial evaluating the influence of PNS on patients with chronic sacroiliac joint syndrome. We believe that PNS on patients with chronic sacroiliac joint syndrome will show promising results regarding pain relief and quality of life in comparison to BMT after 12 months. The design of this trial promises high evidence in comparison to the data to date. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05357300. Registered on April 26, 2022.

Correction: CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial.

PURPOSE: In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS: In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS: In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION: BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Treatment monitoring in gliomas: comparison of dynamic susceptibility-weighted contrast-enhanced and spectroscopic MRI techniques for identifying treatment failure.

OBJECTIVE: To evaluate whether dynamic susceptibility-weighted contrast-enhanced (DSC), dynamic contrast-enhanced (DCE), and proton spectroscopic imaging ((1)H-MRSI) can identify progression and predict treatment failure during follow-up before tumor size changes, contrast agent uptake, or when new lesions become obvious. The aim was also to find out which of the aforementioned techniques had the best diagnostic performance compared with each other and standard magnetic resonance imaging (MRI). MATERIALS AND METHODS: Thirty-seven patients with gliomas (21 women, 16 men; mean age at inclusion, 48 ± 14 years [standard deviation]) were assessed prospectively by (1)H-MRSI (point-resolved spectroscopy), DCE, and DSC perfusion MRI, each after a single dose of gadobenate dimeglumine during follow-up. Histology was available in all cases (resection, N = 18; biopsy, N = 19). All patients with low-grade gliomas (n = 20) did not receive any radio- or chemotherapy after partial resection (n = 7) or biopsy (n = 13), whereas 17 patients with high-grade gliomas had received adjuvant radiotherapy immediately after surgery. Tumor progression (progressive disease, PD) was defined as increase in longest glioma diameter by at least 20% (Response Evaluation Criteria in Solid Tumors), appearance of new lesions, or new contrast-enhancement. DSC, DCE, and MRSI image analyses comprised a detailed semiquantitative region of interest (ROI) analysis of the different parameters. Wilcoxon signed-rank test, Wilcoxon rank sum test, and Cox regression were used for statistical analysis. RESULTS: The median follow-up time was 607 days. Twenty patients showed PD (54%), 8 of 20 with low-grade (40%) and 12 of 17 with high-grade gliomas (71%). In PD, significant positive differences between log2-transformed ROI ratios at the last measurement in comparison to the first measurement (baseline) could be detected for tumor blood flow (P < 0.006) and volume (P < 0.001) derived from DSC and for maximum choline within tumor tissue (P = 0.0029) and Cho/Cr (P = 0.032) but not choline/N-acetyl-aspartate (P = 0.37) derived from MRSI. In contrast, these parameters were not significantly higher at last measurement in stable disease. Also, the differences between last value and baseline were significantly different between PD and stable disease for tumor blood flow (P < 0.004) and volume (P < 0.002) as well as for maximum choline within tumor tissue (P = 0.0011). The best prognostic parameter for PD at Cox analysis was time-dependent difference to baseline of log2 of relative regional cerebral blood flow normalized on gray matter (hazard ratio, 2.67; 95% confidence interval, 1.25-6.08; P = 0.01), while a prognostic value of MRS parameters could not be demonstrated. CONCLUSION: DSC perfusion imaging can identify progression and can predict treatment failure during follow-up of gliomas with the best diagnostic performance.

Biopsy targeting gliomas: do functional imaging techniques identify similar target areas?

OBJECTIVE: Because of the heterogeneous nature of glioma, biopsies performed should be targeted at the most anaplastic region. Several functional magnetic resonance imaging (MRI) or positron emission tomography (PET) techniques have been proposed for identifying the most anaplastic tumor area. However, it is unclear whether the recommended biopsy targets based on these various functional imaging modalities correspond with each other. Thus, the purpose was to evaluate whether they identify similar target areas. MATERIALS AND METHODS: A total of 61 patients with suspected glioma were assessed within 2.3 +/- 3.5 days by MRI, 18F-fluorothymidine-, and 18F-fluorodeoxyglucose-PET. Thirty-five patients underwent gross total resection and 26 were stereotactically biopsied. MRI was performed on a 1.5 Tesla broadband transmit/receive system, using a double-resonant birdcage coil. The MRI protocol comprised of sodium (23Na)-MRI (3D-radial projection imaging), proton spectroscopic imaging (1H-MRSI, point-resolved spectroscopy), arterial spin-labeling (ASL) perfusion MRI, dynamic contrast-enhanced (DCE) MRI, and dynamic-susceptibility-weighted (DSC) perfusion MRI after a single dose each of gadobenate dimeglumine. Also, apparent diffusion coefficient (ADC) maps were processed from diffusion tensor images. Image analysis comprised a detailed semiquantitative region of interest analysis of the different parameter values as well as visual identification of the most conspicuous tumor areas on parameter maps, for example, areas with maximum tumor perfusion, highest metabolite ratios of choline-containing compounds/N-acetyl-aspartate, or lowest ADC values within tumor tissue. Colocalization of these areas was then assessed. RESULTS: Regarding tumor vascularity-related parameters and tumor proliferation-related parameters, the higher the glioma grade the higher were the respective parameters in semiquantitative analysis. ADC values decreased with glioma grade. In the whole study population comprising low- (N = 15) and high-grade gliomas (N = 42), except for 23Na-MRI, there was good (>50%) or perfect (100%) agreement of the tumor areas with highest values on parameter images in the majority of cases (>80%), that is, tumor areas with increased thymidine-uptake and highest choline, both suggestive of increased tumor proliferation, and elevated microcirculation as demonstrated by DSC-, arterial spin-labeling-, and DCE-MRI. 23Na-MRI depicted the highest signal within necrotic tumor areas, but non-necrotic gliomas also showed a perfect agreement in more than 61%. 18F-fluorothymidine-PET, DSC-, and DCE-MRI, diffusion-weighted imaging as well as MR spectroscopic imaging correctly detected no glioma heterogeneity in all 15 histologically proven grade II gliomas but identified suspicious areas in all 3 nonenhancing grade III gliomas. CONCLUSION: Both imaging techniques that depict microcirculation and techniques that visualize proliferation identify similar target areas.

Human brain tumor imaging with a protein-binding MR contrast agent: initial experience.

Gadofosveset is a Gd-based protein-binding blood pool agent with increased relaxivities and blood half-life compared with conventional Gd-based contrast agents (GBCAs). No experience exists about the use of gadofosveset as an extracellular agent. In this report we present the first clinical experience with gadofosveset in enhancing intracranial tumors. Ten patients with different intracranial tumors were examined with a standard dose (0.03 mmol/kg) of gadofosveset compared with a standard dose (0.1 mmol/kg) of conventional GBCA. As a result of its significantly higher relaxivity, gadofosveset could, despite its low dose, achieve a sufficient contrast enhancement. The visual rating of the intensity of enhancement and the contrast to noise ratios were comparable to conventional agents. The detection and delineation of more complex lesions was rated equal. In one nonenhancing low grade astrocytoma an enhancing nodule became visible only 5 h after gadofosvesest injection. As shown in this initial report, contrast-enhanced intracranial tumor imaging is possible with the protein-binding blood pool agent gadofosveset. The agent gives a significant tumor contrast in early postcontrast imaging comparable with conventional agents. As a result of its unique longer lasting contrast, the use of gadofosveset might enable a new approach to imaging mild or nonenhancing tumors.

Yes and PI3K bind CD95 to signal invasion of glioblastoma.

Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.

A rare primary sellar melanoma. Case report.

The authors report on the case of a 37-year-old woman in whom a primary sellar malignant melanoma mimicking a hemorrhagic pituitary macroadenoma was treated. This entity is exceedingly rare; only five cases are described in the literature. The patient presented with rapid deterioration of vision within a 2-week period. After an ophthalmological diagnosis of chiasmal syndrome was made, magnetic resonance (MR) imaging of the head revealed an intra- and suprasellar mass that was elevating and compressing the optic chiasm. Because of the signal heterogeneity of the lesion a hemorrhagic pituitary macroadenoma was assumed; the lesion was transsphenoidally resected. Histological examination of the specimen showed a malignant melanocytic tumor with immunopositivity for S100 protein and HMB-45. Despite extensive staging no other primary melanotic tumor was found. Thus, a primary sellar melanoma was diagnosed. Postoperative MR images demonstrated no residual tumor. For adjuvant therapy the region around the sella turcica received 40.4 Gy stereotactically guided radiation. A 24-month follow-up examination revealed no tumor recurrence. This represents the sixth case of such a lesion reported in the literature, the third case evaluated using MR imaging, and the first case with a progression-free survival of 24 months. Thus, the authors advocate that management of primary sellar melanoma should include gross-total removal and postoperative stereotactic radiotherapy.