Ischemic preconditioning (IPC) is an approach of protection against cerebral ischemia by inducing endogenous cytoprotective machinery. However, few studies in neurogenesis and oligodendrogenesis ...after IPC have been reported, especially the latter. The purpose of this study is to test our hypothesis that IPC may also induce cell proliferation and oligodendrogenesis in the subventricular zone and striatum, as well as to investigate the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) on oligodendrogenesis. IPC was induced in mice by 12-min ischemia through the occlusion of the middle cerebral artery. Newly generated cells were labeled with 5-bromo-2′-deoxyuridine. Our findings demonstrated that IPC stimulated the proliferation of neural stem cells in the subventricular zone, promoted the generation of oligodendrocyte precursor cells in the striatum and corpus callosum/external capsule (CC/EC), and stimulated oligodendrocyte precursor cells differentiation into oligodendrocytes in the striatum and the CC/EC. Furthermore, we describe a crucial role for Nrf2 in IPC-induced oligodendrogenesis in the subventricular zone, striatum, and CC/EC and show for the first time that Nrf2 promoted the migration and differentiation of oligodendrocyte precursor cells into oligodendrocytes in the striatum and CC/EC. Our data imply that IPC stimulates the oligodendrogenesis in the brain and that Nrf2 signaling may contribute to the oligodendrogenesis.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Post-stroke treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be a promising therapy in young animals but this has not been tested in aged subjects, a population at most risk of ...ischemic stroke. Herein we examined the therapeutic efficacy of n-3 PUFAs after distal middle cerebral artery occlusion (dMCAO) in young (10–12 weeks old) and aged (18 months old) mice. Post-ischemic mice were randomly assigned to 4 groups that received: 1) regular food with low content of n-3 PUFAs, 2) intraperitoneal docosahexaenoic acid (DHA, a major component of n-3 PUFAs) injections, 3) Fish oil (FO, containing high concentration of n-3 PUFAs) dietary supplement, or 4) combined treatment with DHA and FO dietary supplement. Long-term neurorestoration induced by n-3 PUFA post-stroke administration and its underlying mechanism(s) were analyzed up to 35 days after dMCAO. Aged mice showed more severe neurological deficits than young mice after dMCAO with histological lesions extended to the striatum. Notably, post-stroke treatment with combined DHA injections and FO dietary supplementation was more effective in reducing brain injury and improving sensorimotor function in aged mice than either treatment alone, albeit to a lesser extent than in the young mice. Unlike the improvement in spatial cognitive function observed in young mice, the combined treatment regimen failed to improve cognitive function in aged mice. The reduction in stroke-induced neurological deficits with n-3 PUFA post-treatment was associated with enhanced angiogenesis, oligodendrogenesis, neuron survival and white matter restoration. Together, these results indicate that the neurological benefits of n-3 PUFA administration after stroke extend to older animals and are associated with improved neuronal survival and brain remodeling, therefore suggesting that post-stroke administration of n-3 PUFAs is a viable clinically relevant treatment option against stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Traumatic brain injury (TBI) is one of the most disabling clinical conditions that could lead to neurocognitive disorders in survivors. Our group and others previously reported that prophylactic ...enrichment of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) markedly ameliorate cognitive deficits after TBI. However, it remains unclear whether a clinically relevant therapeutic regimen with n-3 PUFAs administered after TBI would still offer significant improvement of long-term cognitive recovery. In the present study, we employed the decline of spatial cognitive function as a main outcome after TBI to investigate the therapeutic efficacy of post-TBI n-3 PUFA treatment and the underlying mechanisms. Mice were subjected to sham operation or controlled cortical impact, followed by random assignment to receive the following four treatments: (1) vehicle control; (2) daily intraperitoneal injections of n-3 PUFAs for 2 weeks, beginning 2 h after TBI; (3) fish oil dietary supplementation throughout the study, beginning 1 day after TBI; or (4) combination of treatments (2) and (3). Spatial cognitive deficits and chronic brain tissue loss, as well as endogenous brain repair processes such as neurogenesis, angiogenesis, and oligodendrogenesis, were evaluated up to 35 days after TBI. The results revealed prominent spatial cognitive deficits and massive tissue loss caused by TBI. Among all mice receiving post-TBI n-3 PUFA treatments, the combined treatment of fish oil dietary supplement and n-3 PUFA injections demonstrated a reproducible beneficial effect in attenuating cognitive deficits although without reducing gross tissue loss. Mechanistically, the combined treatment promoted post-TBI restorative processes in the brain, including generation of immature neurons, microvessels, and oligodendrocytes, each of which was significantly correlated with the improved cognitive recovery. These results indicated that repetitive and prolonged n-3 PUFA treatments after TBI are capable of enhancing brain remodeling and could be developed as a potential therapy to treat TBI victims in the clinic.
Background
Treatment of patients with a large number of brain metastases using radiosurgery remains controversial. In this study we sought to conduct a volume matched comparison to evaluate the ...clinical outcome of patients with > 20 brain metastases and compared it with patents with solitary brain tumor form non-small cell lung cancer (NSCLC).
Methods
Between 2014 and 2020, 26 NSCLC patients (925 tumors) underwent stereotactic radiosurgery (SRS) for > 20 metastases in a single procedure (median margin dose = 16 Gy, median cumulative tumor volume = 4.52 cc); 56 patients underwent SRS for a single metastasis (median margin dose = 18 Gy, median volume = 4.74 cc). The overall survival (OS), local tumor control (LC), adverse radiation effect (ARE) risk, and incidence of new tumor development were compared.
Results
No difference in OS was found between patients with > 20 brain metastases (median OS = 15 months) and patients with solitary metastasis (median OS = 12 months; p = 0.3). In the solitary tumor cohort, two of 56 (3.5%) tumors progressed whereas in the > 20 cohort only 3 of 925 (0.3%) tumors showed progression (*p = 0.0013). The rate of new tumor development was significantly higher in patients with > 20 tumors (***p = 0.0001). No significant difference of ARE rate was found (7.5% for > 20 tumors vs. 8.7% for single metastasis).
Conclusions
Patients with > 20 tumors showed significantly better LC with similar OS compared to patients with solitary tumors. Current guidelines that restrict the role of SRS to patients with 1–4 tumors should be revised.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BACKGROUND
Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on ...the risk of developing radiation necrosis (RN) are limited.
METHODS
RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN.
RESULTS
Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow‐up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole‐brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06‐42.38 cm3); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27‐111.22 cm3). Any‐grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio OR, 1.08; 95% confidence interval CI, 1.01‐1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99‐1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17‐2.30; P = .76), prior WBRT, and ICI agents were not statistically significant.
CONCLUSIONS
Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single‐fraction SRS.
The concurrent administration of immune checkpoint inhibitors and stereotactic radiosurgery in patients with renal cell carcinoma brain metastases is safe and well tolerated. Symptomatic radiation necrosis occurred in <15% of patients, and all cases were managed medically.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Emerging evidence suggests that tissue plasminogen activator (tPA), currently the only FDA-approved medication for ischemic stroke, exerts important biological actions on the CNS besides its ...well-known thrombolytic effect. In this study, we investigated the role of tPA on primary neurons in culture and on brain recovery and plasticity after ischemic stroke in mice. Treatment with recombinant tPA stimulated axonal growth in culture, an effect independent of its protease activity and achieved through epidermal growth factor receptor (EGFR) signaling. After permanent focal cerebral ischemia, tPA knockout mice developed more severe sensorimotor and cognitive deficits and greater axonal and myelin injury than wildtype mice, suggesting that endogenously expressed tPA promotes long-term neurological recovery after stroke. In tPA knockoutmice, intranasal administration of recombinant tPA protein 6 hours poststroke and 7 more times at 2 d intervals mitigated white matter injury, improved axonal conduction, and enhanced neurological recovery. Consistent with the proaxonal growth effects observed in vitro, exogenous tPA delivery increased poststroke axonal sprouting of corticobulbar and corticospinal tracts, which might have contributed to restoration of neurological functions. Notably, recombinant mutant tPA-S478A lacking protease activity (but retaining the EGF-like domain) was as effective as wild-type tPA in rescuing neurological functions in tPA knockout stroke mice. These findings demonstrate that tPA improves long-term functional outcomes in a clinically relevant stroke model, likely by promoting brain plasticity through EGFR signaling. Therefore, treatment with the protease-dead recombinant tPA-S478A holds particular promise as a neurorestorative therapy, as the risk for triggering intracranial hemorrhage is eliminated and tPA-S478A can be delivered intranasally hours after stroke.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Traumatic brain injury (TBI) can lead to long-term motor and cognitive dysfunction, which can be at least partly attributed to blood-brain barrier (BBB) disruption. The mechanisms underlying post-TBI ...BBB disruption, however, are poorly understood thus far. Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) is a universally expressed ion transporter that maintains intracellular ion homeostasis by increasing intracellular K+ and Cl−. Having been characterized in stroke models, NKCC1 is activated in various cell types in the ischemic brain, and is thought to mediate BBB disruption, brain edema, and neuronal cell death. In this study, we tested the hypothesis that inhibition of NKCC1 may improve neurological outcomes via protecting against BBB disruption in a TBI mouse model. Adult male C57BL/6 J mice or NKCC1 deficient mice were subjected to controlled cortical impact (CCI). As an alternative to the genetic-based NKCC1 depletion, bumetanide, a selective NKCC1 inhibitor, was administrated (25 mg/kg, i.p.) 15 min after CCI and then every 6 h up to 48 h. Short-term sensorimotor function recovery was determined by rotarod, cylinder test, grid walking and foot fault test. BBB integrity was examined at 48 h post-CCI by measuring Evans blue extravasation, brain water content, and expression levels of tight junction proteins. Our results revealed that administration of bumetanide or genetic depletion of NKCC1 improved short-term neurological recovery against TBI. Bumetanide treatment markedly decreased brain water content and BBB leakage, correlated with reduction of MMP-9 expression and preventing the degradation of tight junction proteins. These findings suggest an important role of NKCC1 activation in mediating BBB disruption after TBI. Thus, NKCC1 inhibition may offer the potential for improving neurological outcomes in clinical TBI.
•NKCC1 contributes to TBI-induced BBB breakdown.•Inhibition of NKCC1 with bumetanide protects BBB integrity after TBI.•Bumetanide attenuates BBB leakage by suppressing MMP9 overproduction post TBI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The role of stereotactic radiosurgery (SRS) for patients with brain metastases from hepatopancreaticobiliary (HPB) cancers has yet to be established. The authors present a single-institution ...experience of patients with HPB cancers who underwent SRS when their cancer spread to the brain.
We surveyed our Gamma Knife SRS data base of 18,000 patients for the years 1987-2022. In total, 19 metastatic HPB cancer patients (13 male) with 76 brain metastases were identified. The median age at SRS was 61 years (range: 48-83). The primary cancer sites were hepatocellular carcinoma (HCC, 11 patients), cholangiocarcinoma (CCC, 2 patients), and pancreatic carcinoma (PCC, 6 patients). The median Karnofsky Performance Score (KPS) was 80 (range: 50-90). Two patients underwent pre-SRS whole-brain fractionated radiation therapy (WBRT) and eight patients underwent pre-SRS surgical resection. All SRS was delivered in single session. The median margin dose was 18 Gy (range: 15-20). The median cumulative tumor volume was 8.1 cc (range: 1.0-44.2).
The median patient overall survival (OS) after SRS was 7 months (range 1-79 months). Four patients had documented local tumor progression after SRS at a median time of 8.5 months (range: 2-15) between SRS and progression. Out of 76 treated tumors, 72 tumors exhibited local control. The local tumor control rate per patient was 78.9%. The local tumor control per tumor was 94.7%. Four patients developed new brain metastases at a median of 6.5 months (range: 2-17) after SRS. No patient experienced adverse radiation effects (AREs). At the last follow-up, 18 patients had died, all from systemic disease progression.
Metastatic spread to the brain from HPB cancers occurs late in the course of the primary disease. In this study, all deceased patients ultimately died from primary disease progression. SRS is a non-invasive strategy that maximally preserves quality of life, and our results reported favorable outcomes compared to the existing literature. SRS should be considered as one of the primary management strategies for patients with brain metastatic spread from HPB cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Melanoma is a complex disease with a high propensity for brain metastatic spread. Stereotactic radiosurgery (SRS) is a minimally invasive procedure to treat intracranial metastasis with a high rate ...of local tumor control. In this report, we describe the ongoing management of a patient with interval development of both new and recurrent brain metastases that required seven SRS procedures for a total of 48 brain metastases during a two-year interval while receiving concurrent immunotherapy with ipilimumab and nivolumab. The most recent imaging of the patient showed three brain areas of likely tumor progression despite maintenance nivolumab, and the treatment was recently changed to encorafenib and binimetinib. Combined management with immunotherapy, initial craniotomy, and repeated SRS for new brain metastases resulted in extended survival while preserving neurological function and reducing adverse treatment effects in a patient with advanced metastatic brain melanoma.
INTRODUCTION: Stereotactic Radiosurgery (SRS) currently is the most widely used neurosurgical strategy for treatment of brain metastases. Many centers still rely on 30-year-old dose volume guidelines ...derived from RTOG 90-05. METHODS: Between 2014 and 2020 330 NSCLC patients (median age = 65 years) with 2910 brain metastases underwent Gamma knife SRS. The number of tumors treated per patient ranged from 1-56 and the total tumor cumulative volume ranged from .05 to 33.09 cc (median = 3.17). The median prescribed tumor margin dose was 18 Gy. RESULTS: Median overall survival after radiosurgery was 15.5 months. Radiological tumor progression was noted 66 out of 2910 tumors (2.27%) in 51 out of 330 patients (15.45%). Tumors were divided into 4 categories based on tumor volumes (<1.5 cc, 1.5-<5 cc, 5-<10 cc, and = 10cc). The effect of margin dose, and % tumor covered in 18 Gy, 20 Gy, and 24 Gy on local tumor control was analyzed for all 4 categories. In tumors with volumes >1.5 cc local tumor control was significantly better (P < 0.05) when =65% of the tumor volume received at least 24 Gy. No relationship was found between tumor control and 75, 90, and 100 % volumes receiving 18 or 20 Gy. CONCLUSIONS: In this study neither conformality of dose delivery nor tumor margin doses were the most important predictors of local tumor control as long as =65% of the tumor volume received at least 24 Gy. This finding can serve as a prescriptive guideline that allows margin doses below the RTOG guidelines, reduces reliance on strict conformality, and improves tumor control.
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