Water-soluble fullerene derivatives mitigate cranial radiation-induced neuroinflammation and cognitive dysfunction.

Gamma knife treatment is a clinically effective, safe, and cost-effective adjunctive therapy for primary malignant brain tumors. For most brain metastases, radiosurgery is the treatment of choice and will result in effective tumor control in more than 90% of treated tumors.

As survival rates have risen for children with malignant primary brain tumors, so has the concern that many survivors have significant permanent cognitive deficits. Cranial irradiation (CRT) has been implicated as the major cause for cognitive dysfunction. To clarify the etiology, incidence, and severity of intellectual compromise in children with brain tumors after CRT, a prospective study was undertaken comparing the neuropsychological outcome in 18 consecutive children with malignant brain tumors treated with CRT to outcome in 14 children harboring brain tumors in similar sites in the nervous system who had not received CRT. Children with cortical or subcortical brain tumors were not eligible for study. Neuropsychological testing was performed after surgery prior to radiotherapy, after radiotherapy, and at 1- and 2-year intervals thereafter. Children who had received CRT had a mean full-scale intelligence quotient (FSIQ) of 105 at diagnosis which fell to 91 by Year 2. Similar declines were noted in their performance intelligence quotient (IQ) and verbal IQ. After CRT, patients demonstrated a statistically significant decline from baseline in FSIQ (p less than 0.02) and verbal IQ (p less than 0.04). Children who had not received CRT did not demonstrate a fall in any cognitive parameter over time. The decline between baseline testing and testing performed at Year 2 in patients who had CRT was inversely correlated with age (p less than 0.02), as younger children demonstrated the greatest loss of intelligence. Children less than 7 years of age at diagnosis had a mean decline in FSIQ of 25 points 2 years posttreatment. No other clinical parameter correlated with the overall IQ or decline in IQ. After CRT, children demonstrated a wide range of dysfunction including deficits in fine motor, visual-motor, and visual-spatial skills and memory difficulties. After CRT, children with brain tumors also demonstrated a fall in a wide range of achievement scores and an increased need, over time, for special help in school. The 2-year results of this study suggest that children with brain tumors treated with CRT are cognitively impaired and that these deficits worsen over time. The younger the child is at the time of treatment, the greater is the likelihood and severity of damage. These children, although not retarded, have a multitude of neurocognitive deficits which detrimentally affects school performance. New treatment strategies are needed for children with malignant brain tumors.

According to the NSD Concept (Ellis, 1966, 1971) it is possible to determine the dose per fraction for a given number of fractions in a given time for a certain biological effect on the normal connective tissue. In many human neoplasms, apart from certain radiosensitive ones such as Hodgkin's disease, it is only possible to achieve tumour tolerance (i.e., local cure) by reaching or exceeding normal tissue (i.e., connective tissue) tolerance. Certain neoplasms are acknowledged to be “radioresistant” to the conventional schedules of radiotherapy. Using the NSD formula it is possible to decide on other schedules the effects of which lie within normal tissue tolerance.

Cognitive dysfunction induced by cranial radiotherapy: mechanisms and therapeutic methods

Radiotherapy is commonly employed to treat cancers of the head and neck and is increasingly used to treat other central nervous system (CNS) disorders. Exceeding the radiation tolerance of normal CNS tissues can result in sequelae contributing to patient morbidity and mortality. Animal studies and clinical experience suggest that neuroinflammation plays a role in the etiology of these effects; however, detailed characterization of this response has been lacking. Therefore, a dose-time investigation of the neuroinflammatory response after single-dose cranial irradiation was performed using C57BL/6 mice. Consistent with previous reports, cranial irradiation resulted in multiphasic inflammatory changes exemplified by increased transcript levels of inflammatory cytokines, along with glial and endothelial cell activation. Cranial irradiation also resulted in acute infiltration of neutrophils and a delayed increase in T cells, MHC II-positive cells, and CD11c-positive cells seen first at 1 month with doses ≥ 15 Gy. CD11c-positive cells were found almost exclusively in white matter and expressed MHC II, suggesting a "mature" dendritic cell phenotype that remained elevated out to 1 year postirradiation. Our results indicate that cranial irradiation leads to persistent neuroinflammatory changes in the C57BL/6 mouse brain that includes unique immunomodulatory cell populations.

Therapeutic effect of boron neutron capture therapy (BNCT) on field cancerized tissue: Inhibition of DNA synthesis and lag in the development of second primary tumors in precancerous tissue around treated tumors in DMBA-induced carcinogenesis in the hamster cheek pouch oral cancer model

In radiation therapy for malignant brain tumours, the dose of radiation that can be safely delivered to a tumour is limited by the radiation tolerance of the adjacent normal brain tissue. Among various radiation modalities to produce local tumour eradication without unacceptable complications, we chose a large, single irradiation dose during the operation (intra-operative radiation therapy, IORT). In contrast to X-ray or Cobalt-60 gamma ray irradiation, IORT with a high-energy electron beam delivered by the Shimadzu 20 MeV betatron provides acceptable dose homogeneity with rapid fall-off of the radiation dose beyond the treatment volume. Thus, IORT has the advantage of precise demarcation of the target volume, minimum damage to surrounding normal tissues, and a high absorbed target dose (15-25 Gy in 5-10 min). On the basis of our experience with 170 patients treated by IORT, we established the treatment indications and method in patients with malignant brain tumours. IORT with a dose of 15-25 Gy was delivered to widely resected tumours followed by external radiation therapy. No acute or subacute complications were observed. Treatment results of 30 patients with glioblastoma treated by IORT (mean 18.3 Gy) combined with external radiation therapy (mean 58.5 Gy) resulted in a median survival of 119 weeks and a 2-year survival rate of 61%.

Tolerance of normal tissue to therapeutic irradiation

A numerical simulation of organ motion and daily setup uncertainties: Implications for radiation therapy

3D conformal radiotherapy in the sagittal plane for centrally located thoracic tumors

Neural Precursor Cells and Central Nervous System Radiation Sensitivity

Clinical radiotherapeutic doses are limited by the tolerance of normal tissues. Patients given a standard treatment exhibit a range of normal tissue reactions, and a better understanding of this individual variation might allow for individualisation of radiotherapeutic prescriptions, with consequent improvement in the therapeutic ratio. At present, there is no simple way to describe normal tissue reactions, which hampers communication between clinic and laboratory and between groups from different centres. There is also no method for comparing the severity of reactions in different normal tissues. This arises largely because there is no definition of a "normal" reaction, an "extreme" reaction or the particular term "over-reactor" (OR). This report proposes definitions for these terms, as well as a simple terminology for describing normal tissue reactions in patients having radiotherapy. The "normal" range represents the individual variation in normal tissue reactions amongst large numbers of patients treated in the same way which is within clinically acceptable limits. The term "OR" is applied to an individual whose reaction is more severe than the normal range but also implies that this forced a major change in the radiotherapeutic prescription or that the reactions were very severe or fatal. A "severe OR" would develop serious problems with a typical radical dose, while an "extreme OR" would have such difficulties at a much lower dose. To describe the normal range, a numerical scale is suggested, from 1 to 5, resistant to sensitive. The term "highly radiosensitive" (HR) is suggested for category 5. An "informal" relative scale, as suggested here, is quick and simple. It should allow comparison between different hospitals, compensate for differences in radiotherapeutic dose and technique and allow comparison of reactions between different anatomical sites. It should be adequate for discriminating patients at the extremes of the normal range from those at the centre. It is hoped that the definitions and terminology proposed here will aid communication in the field of predictive testing of normal tissue radiosensitivity.

Numerous beam directions using 3-D conformal techniques can be employed in treating tumors in the posterior fossa, each with characteristic normal tissue exposure along the entrance and exit trajectory. A representative variety of beam configurations were modeled in a modern computer planning system initially with the entire posterior fossa as the target. These beams were quantitatively scored using criteria based on integral doses for both low dose and high dose effects encompassing a variety of critical normal structures, thus identifying strengths and weaknesses of each beam. By blocking portions of a particular beam accounting for unfavorable scores, a map of "zones" within the posterior fossa ideally treated by a certain beam or beams could be constructed. No universally ideal photon beam arrangement for the entire posterior fossa target could be identified. However, using single beam analysis, the strengths and weaknesses of particular strategies could be quantified. For example, vertex beams treating the cerebellar hemispheres allow the greatest sparing of cochlea and hypothalamus but at the cost of increased low to moderate dose to the supratentorial brain. Using the constructed maps identifying "zones" appropriately treated by a given beam or beams, three-dimensional conformal treatment plans with favorable dose-volume statistics can be designed based on previously defined normal tissue tolerance considerations. It is shown how this approach can be individualized based on specific patient characteristics (e.g., age). We conclude that radiotherapy directed to the posterior fossa can be optimized based on systematic assessment of individual beam contributions to normal tissues. This technique allows fast selection of treatment beams based on known normal tissue anatomical and tolerance information. Further studies will be required regarding long term effects of various radiation doses on specific volumes of normal tissue in order to individualize beam selection. When treating children, knowledgeable consideration of these beam characteristics can help avoid late effects.

Background: According to the development of new treatment modalities, patients with malignant brain tumor have longer survival and they have more chances to have stroke.Study Population: We retrospectively reviewed 509 patients with ischemic stroke and 445 patients with hemorrhagic stroke who visited Kyoto University Hospital between January 2010 and December 2019 and the association with malignant brain tumor was analyzed. The frequency of stroke in 287 patients with primary glioblastoma and 217 patients with metastatic brain tumor was also analyzed.Results: Twenty one (4.1%) patients with ischemic stroke and 26 (5.1%) patients with hemorrhagic stroke patients had malignant brain tumor, and most tumors were either malignant glioma or metastatic brain tumor. A medical history of cranial irradiation was seen in 66.7% of patients with ischemic stroke, and 80% of hemorrhagic stroke occurred within the tumor before starting the treatments. Either ischemic or hemorrhagic stroke occurred in 9.1% of patients with glioblastoma and 4.1% of patients with metastatic brain tumor, and the number of ischemic and hemorrhagic were almost the same. In patients with glioblastoma, nearly half of the stroke cases were associated with bevacizumab. Half of the cases of bevacizumab-related stroke were asymptomatic, while asymptomatic cases were seen in 21.4% for non-bevacizumab cases.Discussion: Stroke is not an uncommon complication in patients with malignant brain tumor but only a restricted number of cases were preventable. Including the cases of bevacizumab-related stroke, which is often asymptomatic, accurate diagnosis and the second prevention would be important.

Purpose: Recently several stereotactic body radiation therapy (SBRT) lung protocols have been developed. To gain insight into the dose tolerance limits and the fractionation schemes, this study is a comparison of the RTOG 0618, 0813, 0915, and Accuray STARS SBRT lung protocols. Method and Materials: To make a fair, unbiased comparison, all selected patients were evaluated according to all six protocol regimens. The DVH Evaluator software tool, which can evaluate a treatment plan according to all selected protocols, was used. Results: When comparing the various dose schemas and normal tissue tolerance limits utilized in currently available protocols, the Accuray STARS protocol incorporates radiobiologically higher dose tolerance limits. There is some discordance in the use of radiobiological equivalent doses as demonstrated with spinal cord limits heavily dependent upon fractionation schema and lung dose limits very similar to standard fractionated target doses. When we compare and contrast the various protocols RTOG 0618 incorporates the highest effective dose, yet some normal tissue tolerance targets are more strict than in other similar trials. Comparative analysis of included patients illustrates that three patients would have received treatment in full compliance with three of six protocols. Another patient was noted to exceed the spinal cord tolerance only for the single fraction arm of RTOG 0915 and skin limit for RTOG 0618, while meeting the esophageal dose limits in three of six protocols. Conclusion: This opens a dialogue regarding SBRT dose limits for the potential delivery of higher effective target doses utilizing the available ranges of acceptable normal tissue tolerance levels for the development of individualized treatment maximizing the risk‐benefit ratio of normal tissue to target dose delivery in an attempt to provide improved outcome for patients.