Interdisciplinary Infection Prevention and Control Bundle in Neurosurgical Patients: Results of a Prospective Cohort Study.

BACKGROUND: Surgical site infections (SSIs) account for one of the most common causes of nosocomial infections. Bundle approaches for infection prevention and control do not capture the full complexity of neurosurgical interventions. OBJECTIVE: To study the efficacy of an interdisciplinary infection prevention and control bundle (IPCB) in neurosurgery. METHODS: This was a prospective, single-center, observational study, analyzing 3 periods: before (2014), during (2017), and after (2019) full implementation of IPCB. IPCB included the following infection prevention measures: preoperative decolonization, patient engagement, operating room (OR) hygiene protocol, and pre-, peri-, and postoperative standard operating procedures (SOPs) while infection control measures included intraoperative sonication, blood culture inoculation, and interdisciplinary SSI management. All neurosurgical patients being readmitted to the hospital for SSIs within 90 days after receiving index surgery were included in the trial (403/9305). RESULTS: Implementation of IPCB resulted in more frequently succeeded pathogen isolation in patients with SSI (2014: 138 isolates in 105 (83%) patients with SSI, 2017: 169 isolates in 124 (91%) patients with SSI, and 2019: 199 isolates in 136 (97%) patients with SSI; P < .001). Proportion of gram-positive SSI and virulence was declining ( P = .041, P = .007). The number of repeated revision surgeries decreased from 26 (20%) in 2014 and 31 (23%) in 2017 to 18 (13%) in 2019 ( P = .085). Significantly, fewer patients experienced sepsis in response to SSI (2014: 12%, 2017: 10%, and 2019: 3.6%, P = .035). In-hospital mortality rate was declining from 12 (9.4%) in 2014 to 9 (6.6%) in 2017 to 5 (3.6%) in 2019 ( P = .148). CONCLUSION: Introducing an interdisciplinary IPCB in neurosurgery leads to a significant reduction of sepsis and decreased in-hospital mortality while a pathogen switch toward gram-negative bacteria was observed. Minimizing diagnostic gap of pathogen detection toward a more efficient anti-infective treatment may be the main reason for the substantial decrease in morbidity and mortality.

[68Ga]Ga-PSMA PET/MRI, histological PSMA expression and preliminary experience with [177Lu]Lu-PSMA therapy in relapsing high-grade glioma.

Purpose: High-grade gliomas (HGG) are still associated with a dismal prognosis. Prostate specific membrane antigen (PSMA) is discussed as a theranostic target for PSMA-directed radioligand therapy ([177Lu]Lu-PSMA RLT). Here, we report on the correlation of [68Ga]Ga-PSMA uptake with histological PSMA expression and on our preliminary experience with [177Lu]Lu-PSMA RLT in relapsing HGG. Methods: Patients with relapsing HGG underwent [68Ga]Ga-PSMA PET/MRI to evaluate eligibility for an individualized treatment approach with [177Lu]Lu-PSMA. Standard uptake values (SUV) for tumor and liver and respective tumor-to-background ratios (compared to the liver) (TBR) on [68Ga]Ga-PSMA PET/MRI were assessed. Eligibility criteria for [177Lu]Lu-PSMA therapy were exhaustion of all standard treatment options available and TBRmax>1.0. In 11 samples, immunohistochemical PSMA expression was determined, quantified using the H-score and correlated with uptake on [68Ga]Ga-PSMA PET/MRI. Results: We included 20 patients with a median age of 53 years (IQR 42-57). The median SUV on [68Ga]Ga-PSMA PET/MRI was 4.5 (3.7-6.2) for SUVmax and 1.4 (1.1-1.7) for SUVmean. The respective TBR was maximum 0.6 (0.4-0.8) and mean 0.3 (0.2-0.4). High TBRmax correlated with increased endothelial PSMA expression [H-score of 65 (62.5-77.5)]. Three patients (15%) presented a TBRmax>1.0 and qualified for [177Lu]Lu-PSMA RLT. No treatment related toxicity was observed. Conclusion: Only a minority of patients with relapsing HGG qualified for [177Lu]Lu-PSMA RLT. Our data demonstrates that PSMA expression in the neo-vasculature corresponds to PSMA uptake on [68Ga]Ga-PSMA PET/MRI and might be used as a screening tool for patient selection. Future prospective studies need to focus the debate on TBRmax thresholds as inclusion criteria for PSMA RLT.

MRI-Based Risk Assessment for Incomplete Resection of Brain Metastases.

Object: Recent studies demonstrated that gross total resection of brain metastases cannot always be achieved. Subtotal resection (STR) can result in an early recurrence and might affect patient survival. We initiated a prospective observational study to establish a MRI-based risk assessment for incomplete resection of brain metastases. Methods: All patients in whom ≥1 brain metastasis was resected were prospectively included in this study (DRKS ID: DRKS00021224; Nov 2020 - Nov 2021). An interdisciplinary board of neurosurgeons and neuroradiologists evaluated the pre- and postoperative MRI (≤48h after surgery) for residual tumor. Extensive neuroradiological analyses were performed to identify risk factors for an unintended STR which were integrated into a regression tree analysis to determine the patients' individual risk for a STR. Results: We included 150 patients (74 female; mean age: 61 years), in whom 165 brain metastases were resected. A STR was detected in 32 cases (19.4%) (median residual tumor volume: 1.36ml, median EORrel: 93.6%), of which 6 (3.6%) were intended STR (median residual tumor volume: 3.27ml, median EORrel: 67.3%) - mainly due to motor-eloquent location - and 26 (15.8%) were unintended STR (uSTR) (median residual tumor volume: 0.64ml, median EORrel: 94.7%). The following risk factors for an uSTR could be identified: subcortical metastasis ≥5mm distant from cortex, diffuse contrast agent enhancement, proximity to the ventricles, contact to falx/tentorium and non-transcortical approaches. Regression tree analysis revealed that the individual risk for an uSTR was mainly associated to the distance from the cortex (distance ≥5mm vs. <5mm: OR 8.0; 95%CI: 2.7 - 24.4) and the contrast agent patterns (diffuse vs. non-diffuse in those with distance ≥5mm: OR: 4.2; 95%CI: 1.3 - 13.7). The preoperative tumor volume was not substantially associated with the extent of resection. Conclusions: Subcortical metastases ≥5mm distant from cortex with diffuse contrast agent enhancement showed the highest incidence of uSTR. The proposed MRI-based assessment allows estimation of the individual risk for uSTR and can help indicating intraoperative imaging.

Regulation of the Receptor Tyrosine Kinase AXL in Response to Therapy and Its Role in Therapy Resistance in Glioblastoma.

The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and SF126 were exposed to temozolomide (TMZ) and radiation (RTX). Receptor modifications in response to therapy were investigated on protein and mRNA levels. TMZ-resistant and RTK-AXL overexpressing cell lines were exposed to increasing doses of TMZ and RTX, with and without RTK-AXL tyrosine kinase inhibitor (TKI). Colorimetric microtiter (MTT) assay and colony formation assay (CFA) were used to assess cell viability. Results showed that the RTK-AXL shedding product, C-terminal AXL (CT-AXL), rises in response to repeated TMZ doses and under hypoxia, acts as a surrogate marker for radio-resistance. Endogenous RTX-AXL overexpression leads to therapy resistance, whereas combination therapy of TZM and RTX with TKI R428 significantly increases therapeutic effects. This data proves the role of RTK-AXL in acquired and intrinsic therapy resistance. By demonstrating that therapy resistance may be overcome by combining AXL TKI with standard treatments, we have provided a rationale for future study designs investigating AXL TKIs in GBM.

Optical Characterization of Sodium Fluorescein In Vitro and Ex Vivo.

OBJECTIVE: The utilization of fluorescein-guided biopsies and resection has been recently discussed as a suitable strategy to improve and expedite operative techniques for the resection of central nervous system (CNS) tumors. However, little is known about the optical properties of sodium fluorescein (NaFl) in human tumor tissue and their potential impact on ex vivo analyses involving fluorescence-based methods. METHODS: Tumor tissue was obtained from a study cohort of an observational study on the utilization of fluorescein-guided biopsy and resection (n=5). The optical properties of fluorescein-stained tissue were compared to the optical features of the dye in vitro and in control samples consisting of tumor tissue of high-grade glioma patients (n=3) without intravenous (i.v.) application of NaFl. The dye-exposed tumor tissues were used for optical measurements to confirm the detectability of NaFl emission ex vivo. The tissue samples were fixed in 4%PFA, immersed in 30% sucrose, embedded in Tissue-Tek OCT compound, and cut to 10 µm cryosections. Spatially resolved emission spectra from tumor samples were recorded on representative slides with a Confocal Laser Scanning Microscope FV1000 (Olympus GmbH, Hamburg, Germany) upon excitation with λexc = 488 nm. RESULTS: Optical measurements of fluorescein in 0.9% sodium chloride (NaCl) under in vitro conditions showed an absorption maximum of λmax abs = 479 nm as detected with spectrophotometer Specord 200 and an emission peak at λmax em = 538 nm recorded with the emCCD detection system of a custom-made microscope-based single particle setup using a 500 nm long-pass filter. Further measurements revealed pH- and concentration-dependent emission spectra of NaFl. Under ex vivo conditions, confocal laser scanning microscopy of fluorescein tumor samples revealed a slight bathochromic shift and a broadening of the emission band. CONCLUSION: Tumor uptake of NaFl leads to changes in the optical properties - a bathochromic shift and broadening of the emission band - possibly caused by the dye's high pH sensitivity and concentration-dependent reabsorption acting as an inner filter of the dye's emission, particularly in the short wavelength region of the emission spectrum where absorption and fluorescence overlap. Understanding the ex vivo optical properties of fluorescein is crucial for testing and validating its further applicability as an optical probe for intravital microscopy, immunofluorescence localization studies, and flow cytometry analysis.