Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Association of baseline frailty status and age with postoperative morbidity and mortality following intracranial meningioma resection.

PURPOSE: Although numerous studies have established advanced patient age as a risk factor for poor outcomes following intracranial meningioma resection, large-scale evaluation of frailty for preoperative risk assessment has yet to be examined. METHODS: Weighted discharge data from the National Inpatient Sample were queried for adult patients undergoing benign intracranial meningioma resection from 2015 to 2018. Complex samples multivariable logistic regression models and receiver operating characteristic curve analysis were performed to evaluate adjusted associations and discrimination of frailty, quantified using the 11-factor modified frailty index (mFI), for clinical endpoints. RESULTS: Among 20,250 patients identified (mean age 60.6 years), 35.4% (n = 7170) were robust (mFI = 0), 34.5% (n = 6985) pre-frail (mFI = 1), 20.1% (n = 4075) frail (mFI = 2), and 10.0% (n = 2020) severely frail (mFI ≥ 3). On univariable analysis, these sub-cohorts stratified by increasing frailty were significantly associated with the development of Clavien-Dindo grade IV (life-threatening) complications (inclusive of those resulting in mortality) (1.3% vs. 3.1% vs. 6.5% vs. 9.4%, p < 0.001) and extended length of stay (eLOS) (15.4% vs. 22.5% vs. 29.3% vs. 37.4%, p < 0.001). Following multivariable analysis, increasing frailty (aOR 1.40, 95% CI 1.17, 1.68, p < 0.001) and age (aOR 1.20, 95% CI 1.05, 1.38, p = 0.009) were both independently associated with development of life-threatening complications or mortality, whereas increasing frailty (aOR 1.20, 95% CI 1.10, 1.32, p < 0.001), but not age, was associated with eLOS. Frailty (by mFI-11) achieved superior discrimination in comparison to age for both endpoints (AUC 0.69 and 0.61, respectively). CONCLUSION: Frailty may be more accurate than advanced patient age alone for prognostication of adverse events and outcomes following intracranial meningioma resection.

Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus.

The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.