Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice.

Despite improved therapeutic methods, CNS toxicity resulting from cancer treatment remains a major cause of post-treatment morbidity. More than half of adult patients with cranial irradiation for brain cancer develop neurobehavioral/cognitive deficits that severely impact quality of life. We examined the neuroprotective effects of the neurosteroid progesterone (PROG) against ionizing radiation (IR)-induced neurobehavioral/cognitive deficits in mice. Male C57/BL mice were exposed to one of two fractionated dose regimens of IR (3Gy×3 or 3Gy×5). PROG (16mg/kg; 0.16mg/g) was given as a pre-, concurrent or post-IR treatment for 14days. Mice were tested for short- and long-term effects of IR and PROG on neurobehavioral/cognitive function on days 10 and 30 after IR treatment. We evaluated both hippocampus-dependent and -independent memory functions. Locomotor activity, elevated plus maze, novel object recognition and Morris water maze tests revealed behavioral deficits following IR. PROG treatment produced improvement in behavioral performance at both time points in the mice given IR. Western blot analysis of hippocampal and cortical tissue showed that IR at both doses induced astrocytic activation (glial fibrillary acidic protein), reactive macrophages/microglia (CD68) and apoptosis (cleaved caspase-3) and PROG treatment inhibited these markers of brain injury. There was no significant difference in the degree of deficit in any test between the two dose regimens of IR at either time point. These findings could be important in the context of patients with brain tumors who may undergo radiotherapy and eventually develop cognitive deficits.

Patient preference for stereotactic radiosurgery plus or minus whole brain radiotherapy for the treatment of brain metastases.

BACKGROUND: Optimal management for limited, non-resectable brain metastases is an evolving area in radiation oncology. Previous data show no difference in survival between stereotactic radiosurgery (SRS) and SRS plus whole-brain radiotherapy (WBRT). Neurocognitive toxicities, treatment duration and tumor recurrence differ and therefore patient values play an important role in decision making. We aim to elicit patient preferences and understand factors important in deciding which treatment to pursue. METHODS: Patients were recruited from 2 centers in North America. Eligibility criteria included ≤4 intracranial lesions and physician judgment that either treatment was appropriate. Those with prior treatment for brain metastases were excluded. A decision board presented the treatments and summarized evidence regarding disease control and toxicity. An option to either take an active or passive role was offered. If taking a passive role, treatment was left to the clinician. If an active role was taken, patients made a decision about whether to receive SRS alone, or in combination with WBRT. A debriefing questionnaire to rank important factors in decision making was then completed. Descriptive statistics summarized findings. RESULTS: A total of 23 patients were enrolled. The majority of patients were male (15/23; 65.2%), had primary lung cancer (15/23; 65.2%) and the mean age was 65.5 years. All patients took an active role in deciding their treatment. The majority of patients (21/23) chose to receive SRS alone. The highest ranked factors were quality of life (9.4/10), ability to maintain functional independence (9.3/10) and influence of treatment on survival (9.2/10). The least important factor was number of trips required to the cancer center (5.0/10). CONCLUSIONS: A patient centered approach to decision making in brain metastases is feasible. Most patients will take an active role in management if relevant information is presented in a clear, understandable manner. When informed, most patients prefer SRS alone rather than SRS + WBRT and identify quality of life, ability to maintain functional independence and influence of treatment on survival as highly important factors in making their decision.

Play-based procedural preparation and support intervention for cranial radiation.

PURPOSE: The primary objective of this study was to examine the relationship between play-based procedural preparation and support intervention and use of sedation in children with central nervous system (CNS) tumors during radiation therapy. The secondary objective was to analyze the cost-effectiveness of the intervention compared to costs associated with daily sedation. METHODS: A retrospective chart review was conducted, and 116 children aged 5-12 years met criteria for inclusion. Outcome measures included the total number of radiation treatments received, the number of treatments received with and without sedation, and the type and duration of interventions, which consisted of developmentally appropriate play, education, preparation, and distraction provided by a certified child life specialist. RESULTS: The results of univariate analyses showed that age, tumor location, and total number and duration of interventions were significantly associated with sedation use during radiation therapy. Multivariate analyses showed that, after adjustment for age, tumor location, and craniospinal radiation, a significant relationship was found between the total number and duration of the interventions and sedation use. The implementation of a play-based procedural preparation and support intervention provided by a certified child life specialist significantly reduced health-care costs by decreasing the necessity of daily sedation. CONCLUSIONS: Support interventions provided by child life specialists significantly decreased both sedation use and the cost associated with daily sedation during cranial radiation therapy in children with CNS tumors. This study supports the value of the child life professional as a play-based developmental specialist and a crucial component of cost-effective healthcare.

Efficacy of therapeutic play for pediatric brain tumor patients during external beam radiotherapy.

OBJECTIVE: External beam radiotherapy (EBRT) is frequently used to improve disease control for pediatric brain tumor patients. However, to facilitate the radiotherapy (RT) procedure, "forced" type interventions including conscious sedation or general anesthesia are frequently used to manage patients' fear and anxiety. The aim of this study was to investigate the effects of therapeutic play (TP) in reducing anxiety for pediatric brain tumor patients treated by EBRT. METHODS: Between April 1st and September 30th, 2009, 19 young brain tumor patients, aged 3-15 years and recommended for RT, were recruited: ten to a control group and nine to the study intervention group. The study group was introduced with TP during EBRT. The Beck Youth Anxiety Inventory and the Faces Anxiety Scale were used to evaluate patients' psychological levels of anxiety. The heart rate variability and salivary cortisol concentrations were used to indicate the patients' physical levels of anxiety. Both the psychological and physiological tests were administered to all subjects before and after the RT procedure. RESULTS: The study group had significantly lower anxiety scores and expressed fewer negative emotions than did the control group before EBRT. CONCLUSIONS: TP can not only improve the quality of medical services but can also reduce costs and staffing demands. In addition, it can help lower young patients' anxiety and fear during medical procedures. As a result, it further decreases the potential negative impacts of hospitalization on these young patients.

Are the psychological needs of adolescent survivors of pediatric cancer adequately identified and treated?

OBJECTIVES: To describe the psychological needs of adolescent survivors of acute lymphoblastic leukemia (ALL) or brain tumor (BT), we examined the following: (i) the occurrence of cognitive, behavioral, and emotional concerns identified during a comprehensive psychological evaluation and (ii) the frequency of referrals for psychological follow-up services to address identified concerns. METHODS: Psychological concerns were identified on measures according to predetermined criteria for 100 adolescent survivors. Referrals for psychological follow-up services were made for concerns previously unidentified in formal assessment or not adequately addressed by current services. RESULTS: Most survivors (82%) exhibited at least one concern across domains: behavioral (76%), cognitive (47%), and emotional (19%). Behavioral concerns emerged most often on scales associated with executive dysfunction, inattention, learning, and peer difficulties. Cranial radiation therapy was associated with cognitive concerns, χ(2) (1, N = 100) = 5.63, p < 0.05. Lower income was associated with more cognitive concerns for ALL survivors, t(47) = 3.28, p < 0.01, and more behavioral concerns for BT survivors, t(48) = 2.93, p < 0.01. Of the survivors with concerns, 38% were referred for psychological follow-up services. Lower-income ALL survivors received more referrals for follow-up, χ(2) (1, N = 41) = 8.05, p < 0.01. Referred survivors had more concerns across domains than non-referred survivors, ALL: t(39) = 2.96, p < 0.01; BT: t(39) = 3.52, p < 0.01. Trends suggest ALL survivors may be at risk for experiencing unaddressed cognitive needs. CONCLUSIONS: Many adolescent survivors of cancer experience psychological difficulties that are not adequately managed by current services, underscoring the need for long-term surveillance. In addition to prescribing regular psychological evaluations, clinicians should closely monitor whether current support services appropriately meet survivors' needs, particularly for lower-income survivors and those treated with cranial radiation therapy.

Effects of alpha-lipoic acid on associative and spatial memory of sham-irradiated and 56Fe-irradiated C57BL/6J male mice.

Cranial irradiation with (56)Fe, a form of space radiation, causes hippocampus-dependent cognitive changes. (56)Fe irradiation also increases reactive oxygen species (ROS) levels, which may contribute to these changes. Therefore, we investigated the effects of the antioxidant alpha lipoic acid (ALA) on cognition following sham-irradiation and irradiation. Male mice were irradiated (brain only) with (56)Fe (3 Gy) or sham-irradiated at 6-9 months of age. Half of the mice remained fed a regular chow and the other half of the mice were fed a caloric-matched diet containing ALA starting two-weeks prior to irradiation and throughout cognitive testing. Following cognitive testing, levels of 3-nitrotyrosine (3NT), a marker of oxidative protein stress, and levels of microtubule-associated protein (MAP-2), a dendritic protein important for cognition, were assessed using immunohistochemistry and confocal microscopy. ALA prevented radiation-induced impairments in spatial memory retention in the hippocampal and cortical dependent water maze probe trials following reversal learning. However, in sham-irradiated mice, ALA treatment impaired cortical-dependent novel object recognition and amygdala-dependent cued fear conditioning. There was a trend towards lower 3NT levels in irradiated mice receiving a diet containing ALA than irradiated mice receiving a regular diet. In the hippocampal dentate gyrus of mice on regular diet, irradiated mice had higher levels of MAP-2 immunoreactivity than sham-irradiated mice. Thus, ALA might have differential effects on the brain under normal physiological conditions and those involving environmental challenges such as cranial irradiation.

Neuropsychological differences between survivors of supratentorial and infratentorial brain tumours.

BACKGROUND: The purpose of this study is to evaluate the relationship between brain tumour location and core areas of cognitive and behavioural functioning for paediatric brain tumour survivors. The extant literature both supports and refutes an association between paediatric brain tumour location and neurocognitive outcomes. We examined neuropsychological test data to identify any differences in neurocognitive and behavioural profile associated with supratentorial versus infratentorial tumour location. METHODS: Following Institutional Review Board approval, the medical records and neuropsychological test data collected between 1997 and 2002 for 70 children treated for brain tumour at Children's Hospital Los Angeles were reviewed. Fifty-one per cent of the participants had tumours located in the supratentorial regions of the brain, whereas 49% had infratentorial tumours. Primary medical treatments involved tumour resection (90%), cranial radiation therapy (76%), chemotherapy (71%), and 59% all three medical procedures. The two tumour location groups did not differ significantly in the cumulative treatment dose of irradiation to the tumour bed or in the dose delivered to the whole brain. Neuropsychological test data included measures of verbal and non-verbal intellectual functioning, attention/working memory, processing speed, verbal and visual memory, fine motor skills, visual-motor integration, academic achievement, and social-emotional functioning. Differences between the two groups were evaluated using anova, t-tests and chi-squared statistical tests. RESULTS: The supratentorial and infratentorial tumour location groups did not differ on measures of intellectual functioning. However, survivors of infratentorial tumours performed more poorly on selected measures of more specific cognitive functions and on parent-report of social-emotional functioning relative to survivors of supratentorial tumours, even when age at diagnosis was held as a covariate. Higher frequency of auditory deficits was noted in the infratentorial tumour group and was associated with lowered academic achievement scores. CONCLUSIONS: The differences by location found in more specific neurocognitive and social-emotional variables, after controlling for age at diagnosis, may possibly reflect tumour location-specific effects. However, this interpretation remains tentative given the limitations in our study and inability to control for the range of medical and treatment-related factors that may have contributed towards the outcomes observed in our sample. At the same time, most of our findings appear consistent with reports from recent studies in this area.

Quality of life: Gamma Knife surgery and whole brain radiation therapy.

Cerebral metastasis of cancers originating outside the brain has traditionally been treated with whole brain radiation therapy (WBRT). Gamma Knife Radiosurgery (GKS) provides safe and effective alternative treatment that is less invasive and has fewer side effects. Both WBRT and GKS are reviewed and discussed in terms of quality of life and health outcomes. The case studies of two individuals who underwent Gamma Knife surgery are presented.

Intensity of CNS treatment for pediatric cancer: prediction of social outcomes in survivors.

PURPOSE: To evaluate the association of central nervous system (CNS) treatment intensity and the social functioning of children who have completed treatment for leukemia, lymphoma, and solid tumors outside the CNS. Furthermore, we expected that these associations would be moderated by child age at diagnosis and gender. METHOD: Peer, teacher, and self-report data were obtained for 82 cancer survivors (age 9-17 years) using classroom rating and nomination procedures that are widely used in research on social development. Information regarding cranial radiation therapy (CRT), intrathecal chemotherapy (ITC), and systemic methotrexate were obtained from medical records and used to create a composite index of CNS treatment intensity. RESULTS: Higher scores on the index of CNS treatment intensity were associated with poorer peer acceptance, fewer friendships, greater social sensitivity-isolation, and diminished leadership-popularity based on peer-report. These associations were stronger for boys and children who were younger (<10 years old) at diagnosis. In contrast, CNS treatment intensity was only predictive of teacher-perceptions of aggressive-disruptive behavior and it was unrelated to social self-perceptions. CONCLUSION: These results suggest that children who receive CRT and ITC are at risk for problematic peer relations, particularly if they are male or younger at diagnosis. Given the stability of poor peer relationships and documented linkages between peer problems and subsequent academic and psychiatric difficulties, clinical services should address these issues. Research is needed to identify mechanisms that account for these outcomes and provide direction for prevention and treatment efforts.

Dental follow-up compliance in a population of irradiated head and neck cancer patients.

OBJECTIVE: This study assessed post-radiation therapy dental follow-up compliance in a population of head and neck cancer patients. STUDY DESIGN: A total of 334 dental charts were retrospectively reviewed to determine the follow-up status of dentate patients. All patients were informed of the importance of returning, after completing radiotherapy, for regular follow-up dental examinations on an indefinite basis. Data regarding compliance with these follow-up instructions over time were obtained. RESULTS: Approximately 170 (51%) of the 334 dentate patients were identified as being lost to dental follow-up. The mean point in time at which follow-up failure occurred was 7.5 months after the initial preirradiation dental examination. CONCLUSION: Dental follow-up compliance may be poor in this irradiated patient population, with follow-up failures potentially occurring less than 1 year after the completion of radiotherapy. Preradiation dental care planning must take into account the likelihood of patients being lost to follow-up.

Felonious sex crime: the possibility of unilateral cerebral irradiation for the offenders.

Some felonious sex crimes might result from compulsions that the perpetrator finds impossible to control. Under judicial systems derived from British law, the court should be extraordinarily careful in mandating any medical procedure. However, if a rapist or child molester voluntarily asks a physician for help, then medical ethics might allow destruction of part of the patient's brain for the purpose of controlling compulsive behaviour. The part of the human brain primarily associated with volition might be near the anterior cingulate sulcus. Could unilateral irradiation of an area near the anterior cingulate sulcus partially destroy the patient's volition? By leaving intact the patient's will based on language and by partially destroying the patient's will based on intuition, could the physician diminish the patient's will to commit felonious sex crimes? Would some patients reject chemical castration but accept unilateral irradiation of an area near the anterior cingulate sulcus?

Quality of life in patients with limited small-cell carcinoma of the lung receiving chemotherapy with or without radiation therapy, for cancer and leukemia group B.

Quality of life was assessed in 57 patients with limited small-cell carcinoma of the lung utilizing psychological scales that measured mood, functional status, and cognitive impairment. These patients received chemotherapy with or without radiotherapy to the primary tumor. All patients received prophylactic cranial radiation. Patients who received the combination of chemotherapy and radiotherapy to both the primary tumor and CNS had an increase in overall survival. However, because of the increased toxicity experienced by these patients, a decrease in quality of life was documented by measures of psychological distress when compared to patients receiving chemotherapy alone. The findings support the importance of utilizing quality of life measures in addition to measures of physical toxicity so that patients can make an informed choice regarding treatment options.