In newly diagnosed IDH-wildtype glioblastoma, the frequency and prognostic relevance of tumor regrowth between resection and the initiation of adjuvant radiochemotherapy are unclear. In this retrospective single-center study we included 64 consecutive cases, for whom magnetic resonance imaging (MRI) was available for both the volumetric assessment of the extent of resection immediately after surgery as well as the volumetric target delineation before the initiation of adjuvant radiochemotherapy (time interval: 15.5 ± 1.9 days). Overall, a median new contrast-enhancement volume was seen in 21/64 individuals (33%, 1.5 ± 1.5 cm3), and new non-contrast lesion volume in 18/64 patients (28%, 5.0 ± 2.3 cm3). A multidisciplinary in-depth review revealed that new contrast-enhancement was either due to (I) the progression of contrast-enhancing tumor remnants in 6/21 patients or (II) distant contrast-enhancing foci or breakdown of the blood–brain barrier in previously non-contrast-enhancing tumor remnants in 5/21 patients, whereas it was unspecific or due to ischemia in 10/21 patients. For non-contrast-enhancing lesions, three of eighteen had progression of non-contrast-enhancing tumor remnants and fifteen of eighteen had unspecific changes or changes due to ischemia. There was no significant association between findings consistent with tumor regrowth and a less favorable outcome (overall survival: 14 vs. 19 months; p = 0.423). These findings support the rationale that analysis of the postsurgical remaining tumor-volume for prognostic stratification should be carried out on immediate postoperative MRI (<72 h), as unspecific changes are common. However, tumor regrowth including distant foci may occur in a subset of IDH-wildtype glioblastoma patients diagnosed per WHO 2021 classification. Thus, MRI imaging prior to radiotherapy should be obtained to adjust radiotherapy planning accordingly.
Pneumococcal meningitis is associated with dysregulation of the coagulation cascade. Previously, we detected upregulation of cerebral plasminogen activator inhibitor-2 (PAI-2) mRNA expression during pneumococcal meningitis. Diverse functions have been ascribed to PAI-2, but its role remains unclear. We analyzed the function of SERPINB2 (coding for PAI-2) in patients with bacterial meningitis, in a well-established pneumococcal meningitis mouse model, using Serpinb2 knockout mice, and in vitro in wt and PAI-2-deficient bone marrow-derived macrophages (BMDMs). We measured PAI-2 in cerebrospinal fluid of patients, and performed functional, histopathological, protein and mRNA expression analyses in vivo and in vitro. We found a substantial increase of PAI-2 concentration in CSF of patients with pneumococcal meningitis, and up-regulation and increased release of PAI-2 in mice. PAI-2 deficiency was associated with increased mortality in murine pneumococcal meningitis and cerebral hemorrhages. Serpinb2−/− mice exhibited increased C5a levels, but decreased IL-10 levels in the brain during pneumococcal infection. Our in vitro experiments confirmed increased expression and release of PAI-2 by wt BMDM and decreased IL-10 liberation by PAI-2-deficient BMDM upon pneumococcal challenge. Our data show that PAI-2 is elevated during in pneumococcal meningitis in humans and mice. PAI-2 deficiency causes an inflammatory imbalance, resulting in increased brain pathology and mortality.
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