scholarly journals An Updated Review on Memantine Efficacy in Reducing Cognitive Dysfunction of Whole-brain Irradiation for Adult Patients with Brain metastasis

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Anya jafari ◽  
Zahra Siavashpour ◽  
Mohammad Houshyari
Keyword(s):  
Brain Metastasis ◽  
Verbal Learning ◽  
Whole Brain Radiotherapy ◽  
Protective Effects ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
Delayed Recognition

Context: Increased survival of patients with cancer raises the need to pay attention to long-term side effects. Patients with brain metastasis experienced cognition failure after whole-brain radiotherapy. This review aimed at concluding the efficacy of Memantine in preserving cognitive function by reducing the brain toxicity of whole-brain radiotherapy for metastatic brain cancers. Evidence Acquisition: Published studies evaluating memantine protective effects during brain metastasis radiotherapy were searched for in scientific databases (e.g., Embase, PubMed, Cochrane database, Google Scholar, Scopus) using keywords including whole-brain radiotherapy and Memantine. Results: A total of 4 prospective clinical trials were included in the review. Effects of Memantine on cognition tests were evaluated in these trials. A significantly better Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recognition at months 6 was achieved in RTOG 0614 and NRG CC001. Longer time to cognitive decline was found in the memantine arm of the RTOG trial and was statistically significant. Memantine effects were not statistically significant before 2 months. Conclusions: It seems reasonable to consider Memantine during radiation to prevent long-term cognitive failure in patients with brain metastasis due to the current results. Memantine improves cognition function during whole-brain radiotherapy (WBRT) without adding irreparable complications.

scholarly journals Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Javier Franco-Pérez ◽  
Sergio Montes ◽  
Josué Sánchez-Hernández ◽  
Paola Ballesteros-Zebadúa
Keyword(s):  
Prefrontal Cortex ◽  
Gabaa Receptor ◽  
Whole Brain Radiotherapy ◽  
Gabab Receptors ◽  
Gamma Aminobutyric Acid ◽  
Secondary Effects ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy

Abstract Background Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. Methods Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann–Whitney U test (p < 0.05). Results WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusion Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

scholarly journals Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

2020 ◽  
Author(s):  
JAVIER FRANCO PEREZ ◽  
SERGIO MONTES ◽  
JOSUE SANCHEZ-HERNANDEZ ◽  
PAOLA BALLESTEROS-ZEBADUA
Keyword(s):  
Prefrontal Cortex ◽  
Gabaa Receptor ◽  
Whole Brain Radiotherapy ◽  
Gabab Receptors ◽  
Gamma Aminobutyric Acid ◽  
Secondary Effects ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy

Abstract Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes.Methods: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Equivalent Dose= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05).Results: WBI with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation.Conclusion: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

scholarly journals Are there still indications for whole brain irradiation in 2021?

2021 ◽  
Author(s):  
Karin Dieckmann ◽  
Harald Herrmann
Keyword(s):  
Brain Metastases ◽  
Whole Brain Radiotherapy ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Patients With Cancer ◽  
Brain Radiotherapy ◽  
Precision Therapy ◽  
Randomized Control ◽  
Neurocognitive Decline

SummaryBrain metastases (BM) are the most frequent intracranial tumors in adults. About 10–20% of the patients with cancer will develop them. Historically, most of the patients with brain metastases were treated with whole brain radiotherapy (WBRT). The intention was to control the metastases and to eliminate distant micrometastases. Randomized control trials showed no difference in survival in patients with single and oligometastases treated with WBRT compared with stereotactic radiosurgery (SRS). To avoid treatment-related toxicities with neurocognitive decline, indications for WBRT are changing. High precision therapy with SRS or postoperative stereotactic treatments have become increasingly important. Only in exceptional cases is WBRT still the treatment of choice.

scholarly journals EXTH-08. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi84
Author(s):  
Xi Feng ◽  
Sonali Gupta ◽  
David Chen ◽  
Zoe Boosalis ◽  
Sharon Liu ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Memory Deficits ◽  
Protective Effects ◽  
Whole Brain Irradiation ◽  
Synaptic Loss ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
The Brain ◽  
Therapeutic Avenue

Abstract Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.

scholarly journals Replacement of microglia by monocyte-derived macrophages prevents long-term memory deficits after therapeutic irradiation

2019 ◽  
Author(s):  
Xi Feng ◽  
David Chen ◽  
Sonali Gupta ◽  
Sharon Liu ◽  
Nalin Gupta ◽  
...  
Keyword(s):  
Memory Deficits ◽  
Intermediate Phenotype ◽  
Long Term Memory ◽  
Protective Effects ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
Therapeutic Irradiation ◽  
The Brain

AbstractResident microglia of the brain have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacologic depletion of microglia during therapeutic whole-brain irradiation prevents synaptic loss and rescues recognition memory deficits but the mechanisms behind these protective effects are unknown. Here we demonstrate that after a combination of therapeutic whole-brain irradiation and microglia depletion, macrophages originating from circulating monocytes engraft into the brain and replace the microglia pool. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. Importantly, the brain-engrafted macrophages have a reduced phagocytic activity for synaptic compartments compared to the activated microglia from irradiated brains, which in turn prevent the aberrant and chronic synapse loss that results in radiation-induced memory deficits. These results are the first to demonstrate that replacement of microglia by brain-engrafted macrophages represent a potential therapeutic avenue for the treatment of brain radiotherapy induced cognitive deficits.

scholarly journals Individual 3D-printed fixation masks for radiotherapy: first clinical experiences

2021 ◽  
Author(s):  
M. Mattke ◽  
D. Rath ◽  
M. F. Häfner ◽  
R. Unterhinninghofen ◽  
F. Sterzing ◽  
...  
Keyword(s):  
Whole Brain Radiotherapy ◽  
The Body ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
Whole Brain Radiation ◽  
Thermoplastic Mask ◽  
Position Correction ◽  
3D Printed

Abstract Purpose To show the feasibility of 3D-printed fixation masks for whole brain radiation therapy in a clinical setting and perform a first comparison to an established thermoplastic mask system. Methods Six patients were irradiated with whole brain radiotherapy using individually 3D-printed masks. Daily image guidance and position correction were performed prior to each irradiation fraction. The vectors of the daily position correction were compared to two collectives of patients, who were irradiated using the standard thermoplastic mask system (one cohort with head masks; one cohort with head and neck masks). Results The mean systematic errors in the experimental cohort ranged between 0.59 and 2.10 mm which is in a comparable range to the control groups (0.18 mm–0.68 mm and 0.34 mm–2.96 mm, respectively). The 3D-printed masks seem to be an alternative to the established thermoplastic mask systems. Nevertheless, further investigation will need to be performed. Conclusion The prevailing study showed a reliable and reproducible interfractional positioning accuracy using individually 3D-printed masks for whole brain irradiation in a clinical routine. Further investigations, especially concerning smaller target volumes or other areas of the body, need to be performed before using the system on a larger basis.

scholarly journals Functional role of brain-engrafted macrophages against brain injuries

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xi Feng ◽  
Elma S. Frias ◽  
Maria S. Paladini ◽  
David Chen ◽  
Zoe Boosalis ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Brain Injuries ◽  
Memory Loss ◽  
Whole Brain Radiotherapy ◽  
Intermediate Phenotype ◽  
Protective Effects ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
Bone Marrow Chimeras

Abstract Background Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown. Methods CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy. Results After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss. Conclusions Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.

scholarly journals SCIDOT-04. REPLACEMENT OF MICROGLIA BY BRAIN-ENGRAFTED MACROPHAGES PREVENTS MEMORY DEFICITS AFTER THERAPEUTIC WHOLE-BRAIN IRRADIATION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi273-vi273
Author(s):  
Xi Feng ◽  
Sonali Gupta ◽  
David Chen ◽  
Zoe Boosalis ◽  
Sharon Liu ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Memory Deficits ◽  
Protective Effects ◽  
Whole Brain Irradiation ◽  
Synaptic Loss ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
The Brain ◽  
Therapeutic Avenue

Abstract Microglia have a distinct origin compared to blood circulating myeloid cells. Under normal physiological conditions, microglia are maintained by self-renewal, independent of hematopoietic progenitors. Following genetic or pharmacologic depletion, newborn microglia derive from the local residual pool and quickly repopulate the entire brain. The depletion of brain resident microglia during therapeutic whole-brain irradiation fully prevents irradiation-induced synaptic loss and recognition memory deficits but the mechanisms driving these protective effects are unknown. Here, we demonstrate that after CSF-1R inhibitor-mediated microglia depletion and therapeutic whole-brain irradiation, circulating monocytes engraft into the brain and replace the microglia pool. These monocyte-derived brain-engrafted macrophages have reduced phagocytic activity compared to microglia from irradiated brains, but similar to locally repopulated microglia without brain irradiation. Transcriptome comparisons reveal that brain-engrafted macrophages have both monocyte and embryonic microglia signatures. These results suggest that monocyte-derived brain-engrafted macrophages represent a novel therapeutic avenue for the treatment of brain radiotherapy-induced cognitive deficits.

scholarly journals Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

2020 ◽  
Author(s):  
Javier Franco-Pérez ◽  
Sergio Montes ◽  
Josué Sanchez-Hernández ◽  
Paola Ballesteros-Zebadúa
Keyword(s):  
Prefrontal Cortex ◽  
Gabaa Receptor ◽  
Whole Brain Radiotherapy ◽  
Gabab Receptors ◽  
Gamma Aminobutyric Acid ◽  
Secondary Effects ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy

Abstract Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are both highly connected to the hypothalamus and its regulatory processes. Methods: Male Wistar rats were exposed to whole-brain irradiation with 11 Gy (BED= 72Gy). After one month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, glutamine, in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the relative expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p<0.05). Results: Whole-brain irradiation with 11Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus, one month after exposure. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significantly increased levels of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. Conclusions: Our findings confirm that whole-brain irradiation can affect rat brain regions differently and opens new avenues for study. After one month, WBI decreases inhibitory neurotransmission in the hypothalamus and, conversely, increases excitatory neurotransmission in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex both indicate a modified neurochemical balance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma

1989 ◽  
Vol 71 (1) ◽  
pp. 1-9 ◽  
Author(s):  
William R. Shapiro ◽  
Sylvan B. Green ◽  
Peter C. Burger ◽  
M. Stephen Mahaley ◽  
Robert G. Selker ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Whole Brain Radiotherapy ◽  
Postoperative Treatment ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Brain Radiotherapy ◽  
Significant Survival ◽  
To Receive

Within 3 weeks of definitive surgery, 571 adult patients with histologically confirmed, supratentorial malignant gliomas were randomly assigned to receive one of three chemotherapy regimens: BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) alone, alternating courses (every 8 weeks) of BCNU and procarbazine, or BCNU plus hydroxyurea alternating with procarbazine plus VM-26 (epipodophyllotoxin). Patients accrued in 1980 and 1981 were to receive 6020 rads of whole-brain radiotherapy concurrent with the first course of chemotherapy. Patients accrued in 1982 and 1983 were randomly assigned to receive either whole-brain irradiation as above, or 4300 rads of whole-brain radiotherapy plus 1720 rads coned down to the tumor volume. The data were analyzed for the total randomized population and separately for the 510 patients, termed the “Valid Study Group (VSG),” who met protocol eligibility specifications (including central pathology review), 80% of whom had glioblastoma multiforme. The median survival times from time of randomization for the three chemotherapy groups of the VSG ranged from 11.3 to 13.8 months, and 29% to 37% of the patients survived for 18 months (life-table estimate); the differences between these groups were not statistically significant. Survival differences between the radiotherapy groups were small and not statistically significant. It is concluded that, for malignant glioma, giving part of the radiotherapy by coned-down boost is as effective as full whole-brain irradiation, and that multiple-drug chemotherapy as outlined in this protocol conferred no significant survival advantage over BCNU alone.

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