BACKGROUND: The landscape of brain metastases radiotherapy is evolving, with a shift away from whole-brain radiotherapy (WBRT) toward targeted stereotactic approaches aimed at preserving neurocognitive functions and maintaining overall quality of life. For patients with multiple metastases, especially in cases where targeted radiotherapy is no longer feasible due to widespread dissemination, the concept of hippocampal sparing radiotherapy (HA_WBRT) gains prominence. METHODS: In this narrative review we explore the role of the hippocampi in memory formation and the implications of their postradiotherapy lateral damage. We also consider the potential advantages of selectively sparing one hippocampus during whole-brain radiotherapy (WBRT). Additionally, by systematic evaluation of relevant papers published on PubMed database over last 20 years, we provide a comprehensive overview of the various changes that can occur in the left or right hippocampus as a consequence of radiotherapy. RESULTS: While it is important to note that various neurocognitive functions are interconnected throughout the brain, we can discern certain specialized roles of the hippocampi. The left hippocampus appears to play a predominant role in verbal memory, whereas the right hippocampus is associated more with visuospatial memory. Additionally, the anterior part of the hippocampus is more involved in episodic memory and emotional processing, while the posterior part is primarily responsible for spatial memory and pattern separation. Notably, a substantial body of evidence demonstrates a significant correlation between post-radiotherapy changes in the left hippocampus and subsequent cognitive decline in patients. CONCLUSION: In the context of individualized palliative radiotherapy, sparing the unilateral (specifically, the left, which is dominant in most individuals) hippocampus could expand the repertoire of strategies available for adapted WBRT in cases involving multiple brain metastases where stereotactic radiotherapy is not a viable option. Prospective ongoing studies assessing various memory-sparing radiotherapy techniques will define new standard of radiotherapy care of patients with multiple brain metastases.

• Klíčová slova
• brain metastases, hippocampus, neurocognitive function, unilateral, whole brain radiotherapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Experimental studies in animals provide relevant knowledge about pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced injury can alter neuronal, glial cell population, brain vasculature and may lead to molecular, cellular and functional consequences. Regarding to its fundamental role in the formation of new memories, spatial navigation and adult neurogenesis, the majority of studies have focused on the hippocampus. Most recent findings in cranial radiotherapy revealed that hippocampal avoidance prevents radiation-induced cognitive impairment of patients with brain primary tumors and metastases. However, numerous preclinical studies have shown that this problem is more complex. Regarding the fact, that the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is highly important to investigate molecular, cellular and functional changes in different brain regions and their integration at clinically relevant doses and schedules. Here, we provide a literature review in order support the translation of preclinical findings to clinical practice and improve the physical and mental status of patients with brain tumors.

• MeSH
• centrální nervový systém patologie   účinky záření   MeSH
• ionizující záření MeSH
• kognitivní poruchy etiologie   patologie   MeSH
• lidé MeSH
• nádory mozku patologie   radioterapie   MeSH
• nemoci mozku etiologie   patologie   MeSH
• radiační poranění etiologie   patologie   MeSH
• sekundární malignity etiologie   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Brain and nervous system cancers in children represent the second most common neoplasia after leukemia. Radiotherapy plays a significant role in cancer treatment; however, the use of such therapy is not without devastating side effects. The impact of radiation-induced damage to the brain is multifactorial, but the damage to neural stem cell populations seems to play a key role. The brain contains pools of regenerative neural stem cells that reside in specialized neurogenic niches and can generate new neurons. In this review, we describe the advances in radiotherapy techniques that protect neural stem cell compartments, and subsequently limit and prevent the occurrence and development of side effects. We also summarize the current knowledge about neural stem cells and the molecular mechanisms underlying changes in neural stem cell niches after brain radiotherapy. Strategies used to minimize radiation-related damages, as well as new challenges in the treatment of brain tumors are also discussed.

• Klíčová slova
• brain and nervous system cancers, neural stem cells, neurogenic niches, radiotherapy, sparing of neurogenic regions,
• MeSH
• lidé MeSH
• mozek cytologie   účinky záření   MeSH
• nádory mozku radioterapie   MeSH
• nervové kmenové buňky cytologie   účinky záření   MeSH
• neurogeneze MeSH
• radioterapie škodlivé účinky   metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Radiotherapy plays a significant role in brain cancer treatment; however, the use of this therapy is often accompanied by neurocognitive decline that is, at least partially, a consequence of radiation-induced damage to neural stem cell populations. Our findings describe features that define the response of neural stem cells (NSCs) to ionizing radiation. We investigated the effects of irradiation on neural stem cells isolated from the ventricular-subventricular zone of mouse brain and cultivated in vitro. Our findings describe the increased transcriptional activity of p53 targets and proliferative arrest after irradiation. Moreover, we show that most cells do not undergo apoptosis after irradiation but rather cease proliferation and start a differentiation program. Induction of differentiation and the demonstrated potential of irradiated cells to differentiate into neurons may represent a mechanism whereby damaged NSCs eliminate potentially hazardous cells and circumvent the debilitating consequences of cumulative DNA damage.

• Klíčová slova
• apoptosis, differentiation, ionizing radiation, neural stem cells, proliferation, proliferative arrest,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Cellular senescence and the senescence-associated secretory phenotype (SASP) may contribute to the development of radiation therapy-associated side effects in the lung and blood vessels by promoting chronic inflammation. In the brain, inflammation contributes to the development of neurologic disease, including Alzheimer's disease. In this study, we investigated the roles of cellular senescence and Δ133p53, an inhibitory isoform of p53, in radiation-induced brain injury. METHODS: Senescent cell types in irradiated human brain were identified with immunohistochemical labeling of senescence-associated proteins p16INK4A and heterochromatin protein Hp1γ in 13 patient cases, including 7 irradiated samples. To investigate the impact of radiation on astrocytes specifically, primary human astrocytes were irradiated and examined for expression of Δ133p53 and induction of SASP. Lentiviral expression of ∆133p53 was performed to investigate its role in regulating radiation-induced cellular senescence and astrocyte-mediated neuroinflammation. RESULTS: Astrocytes expressing p16INK4A and Hp1γ were identified in all irradiated tissues, were increased in number in irradiated compared with untreated cancer patient tissues, and had higher labeling intensity in irradiated tissues compared with age-matched controls. Human astrocytes irradiated in vitro also experience induction of cellular senescence, have diminished Δ133p53, and adopt a neurotoxic phenotype as demonstrated by increased senescence-associated beta-galactosidase activity, p16INK4A, and interleukin (IL)-6. In human astrocytes, Δ133p53 inhibits radiation-induced senescence, promotes DNA double-strand break repair, and prevents astrocyte-mediated neuroinflammation and neurotoxicity. CONCLUSIONS: Restoring expression of the endogenous p53 isoform, ∆133p53, protects astrocytes from radiation-induced senescence, promotes DNA repair, and inhibits astrocyte-mediated neuroinflammation.

• Klíčová slova
• IL-6, astrocytes, p53 isoform, radiation-induced brain injury, senescence,
• MeSH
• astrocyty metabolismus   účinky záření   MeSH
• kraniální ozáření škodlivé účinky   MeSH
• kultivované buňky MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory mozku radioterapie   MeSH
• protein - isoformy metabolismus   MeSH
• radiační poranění metabolismus   MeSH
• stárnutí buněk účinky záření   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH
• protein - isoformy MeSH
• TP53 protein, human MeSH Prohlížeč

INTRODUCTION: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT. METHOD: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre. RESULTS: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance. CONCLUSION: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.

• MeSH
• hipokampus diagnostické zobrazování   MeSH
• léčba šetřící orgány * MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory mozku diagnostické zobrazování   patologie   radioterapie   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH

Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.

• Klíčová slova
• apoptosis, hippocampus, lithium, paediatric oncology, radiotherapy,
• MeSH
• apoptóza účinky léků   účinky záření   MeSH
• chlorid lithný aplikace a dávkování   farmakologie   MeSH
• hipokampus cytologie   účinky léků   účinky záření   MeSH
• kontrolní body buněčného cyklu účinky léků   účinky záření   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nervové kmenové buňky cytologie   účinky léků   účinky záření   MeSH
• neurogeneze účinky léků   fyziologie   účinky záření   MeSH
• novorozená zvířata MeSH
• poškození DNA účinky léků   účinky záření   MeSH
• proliferace buněk účinky léků   účinky záření   MeSH
• průtoková cytometrie MeSH
• radioizotopy kobaltu MeSH
• techniky in vitro MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chlorid lithný MeSH
• radioizotopy kobaltu MeSH

BACKGROUND: The hippocampus is considered as the main radiosensitive brain structure responsible for postradiotherapy cognitive decline. We prospectively assessed correlation of memory change to hippocampal N-acetylaspartate (h-tNAA) concentration, a neuronal density and viability marker, by (1)H-MR spectroscopy focused on the hippocampus. METHODS: Patients with brain metastases underwent whole brain radiotherapy (WBRT) to a dose of 30 Gy in ten fractions daily. Pre-radiotherapy (1)H-MR spectroscopy focused on the h-tNAA concentration and memory testing was performed. Memory was evaluated by Auditory Verbal Learning Test (AVLT) and Brief Visuospatial Memory Test-Revised (BVMT-R). Total recall, recognition and delayed recall were reported. The both investigation procedures were repeated 4 months after WBRT and the h-tNAA and memory changes were correlated. RESULTS: Of the 20 patients, ten passed whole protocol. The h-tNAA concentration significantly decreased from pre-WBRT 8.9, 8.86 and 8.88 [mM] in the right, left and both hippocampi to 7.16, 7.65 and 7.4 after WBRT, respectively. In the memory tests a significant decrease was observed in AVLT total-recall, BVMT-R total-recall and BVMT-R delayed-recall. Weak to moderate correlations were observed between left h-tNAA and AVLT recognition and all BVMT-R subtests and between the right h-tNAA and AVLT total-recall. CONCLUSIONS: A significant decrease in h-tNAA after WBRT was proven by (1)H-MR spectroscopy as a feasible method for the in vivo investigation of radiation injury. Continuing patient recruitment focusing on other cognitive tests and metabolites is needed.

• MeSH
• biologické markery analýza   MeSH
• hipokampus účinky záření   MeSH
• Kaplanův-Meierův odhad MeSH
• kognitivní poruchy diagnóza   etiologie   MeSH
• kraniální ozáření škodlivé účinky   MeSH
• kyselina aspartová analogy a deriváty   analýza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• nádory mozku mortalita   radioterapie   sekundární   MeSH
• neuropsychologické testy MeSH
• paměť MeSH
• protony MeSH
• radiační poranění diagnóza   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• kyselina aspartová MeSH
• N-acetylaspartate MeSH Prohlížeč
• protony MeSH

The goal of this review is to summarize the rationale for and feasibility of hippocampal sparing techniques during brain irradiation. Radiotherapy is the most effective non-surgical treatment of brain tumors and with the improvement in overall survival for these patients over the last few decades, there is an effort to minimize potential adverse effects leading to possible worsening in quality of life, especially worsening of neurocognitive function. The hippocampus and associated limbic system have long been known to be important in memory formation and pre-clinical models show loss of hippocampal stem cells with radiation as well as changes in architecture and function of mature neurons. Cognitive outcomes in clinical studies are beginning to provide evidence of cognitive effects associated with hippocampal dose and the cognitive benefits of hippocampal sparing. Numerous feasibility planning studies support the feasibility of using modern radiotherapy systems for hippocampal sparing during brain irradiation. Although results of the ongoing phase II and phase III studies are needed to confirm the benefit of hippocampal sparing brain radiotherapy on neurocognitive function, it is now technically and dosimetrically feasible to create hippocampal sparing treatment plans with appropriate irradiation of target volumes. The purpose of this review is to provide a brief overview of studies that provide a rationale for hippocampal avoidance and provide summary of published feasibility studies in order to help clinicians prepare for clinical usage of these complex and challenging techniques.

• MeSH
• celková dávka radioterapie MeSH
• hipokampus účinky záření   MeSH
• kraniální ozáření * MeSH
• léčba šetřící orgány * MeSH
• lidé MeSH
• nádory mozku radioterapie   MeSH
• plánování radioterapie pomocí počítače * MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Several studies focusing on brain irradiation are in progress. Reflecting updates of relevant outcomes in palliative treatment of patients suffering from brain metastases, the primary objective of these studies is the evaluation of neurocognitive function and quality of life. Improvements of technology in radiation oncology allows us to spare the hippocampal region while appropriately irradiating other parts of brain tissue. Irradiation of the hippocampus region is likely to lead to manifestations of adverse events with a subsequent impact on patient's quality of life, which is in fact an improper approach in palliative medicine. Ongoing studies evaluate results of hippocampus avoiding radiotherapy compared to standard whole brain radiotherapy. Incorporation of neurocognitive function assessment may result in the confirmation of superiority of sparing the region of hippocampus and thus change current style of providing brain irradiation.

• Klíčová slova
• Brain metastases, Decision-making, Personalized medicine, Whole brain radiotherapy,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH